CN116194145A - Methods of diagnosing cancer using AXL decoy receptor - Google Patents

Methods of diagnosing cancer using AXL decoy receptor Download PDF

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CN116194145A
CN116194145A CN202180064019.0A CN202180064019A CN116194145A CN 116194145 A CN116194145 A CN 116194145A CN 202180064019 A CN202180064019 A CN 202180064019A CN 116194145 A CN116194145 A CN 116194145A
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cancer
axl
treatment
leu
gas6
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盖尔·麦金太尔
雷·塔比比亚扎
伊丽莎白·加德纳
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Alaviv
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Abstract

The present invention provides therapeutic and diagnostic methods and compositions for the treatment of metastatic cancer in humans. In particular, the invention provides methods of treatment and methods for determining whether an individual suffering from cancer is responsive to an AXL decoy protein-based therapy, methods of predicting responsiveness of an individual suffering from cancer to a therapy comprising an AXL decoy protein, and methods of selecting a therapy for an individual suffering from cancer.

Description

Methods of diagnosing cancer using AXL decoy receptor
RELATED APPLICATIONS
The present application claims the benefit of U.S. provisional application No. 63/053,679, filed 7/19 2020, which is incorporated herein by reference in its entirety.
Sequence listing
The present application contains a sequence listing of files (ST 25 format text files) presented herein in the form of "paper copies" (PDF files) and in computer readable form containing reference sequences (SEQ ID NOs: 1 and 2). The sequence listing is shown using the standard three letter code for amino acids as defined in 37 c.f.r.1.822.
Statement regarding federally sponsored research or development
This study was supported by the new company product development prize (New Company Product Development Award) DP150127 by the institute of cancer prevention and research (Cancer Prevention & Research Institute of Texas) in texas, usa. The state of texas in the united states may have rights to any patent issued for this application.
Technical Field
Cancer is a group of diseases involving abnormal cell growth with the potential to spread or invade other parts of the body. Abnormal growth that forms discrete tumor masses (i.e., does not contain cysts or liquid areas) is defined as a solid tumor. Solid tumors may be benign (non-cancerous) or malignant (cancerous). Different types of solid tumors are named for the cell types that form them. Examples of solid tumors are sarcomas, epithelial cancers (carbioma) and lymphomas. Cancers derived from either of two blood cell lineages (bone marrow and lymph) are defined as hematological malignancies. Such hematological malignancies are also known as hematological or liquid tumors. Examples of liquid tumors include multiple myeloma, acute leukemia (e.g., 11q23 positive acute leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia (acute myelocytic leukemia), acute myelogenous leukemia (acute myelogenous leukemia) and myeloblastic leukemia, promyelocytic leukemia, myelomonocytic leukemia (myelomonocytic leukemia), monocytic leukemia and erythroleukemia), chronic leukemia (e.g., chronic myelogenous leukemia (chronic myelocytic), chronic myelogenous leukemia (chronic myelogenous leukemia) and chronic lymphocytic leukemia), polycythemia vera, lymphoma, hodgkin's lymphoma, non-hodgkin's lymphoma (indolent (high grade) and advanced forms), waldenstrom's macroglobulinemia, heavy chain disease, myelodysplastic syndrome, hairy cell leukemia and myelodysplasia.
Cancer is not a single cell disease, but rather is the result of a complex interaction of tumor cells with surrounding stroma and immune cells. The treatments available to cancer patients are severely dependent on combination therapies including surgery, cytoreductive therapy (cytoreductive therapy) and cytotoxic chemotherapy. Unfortunately, while effective in some cases, side effects on normal tissues often manifest as dose-limiting toxicity and prevent tumor eradication. And even when the side effects of these different therapies can be managed, long-lasting responses tend to be elusive; this is especially true for the treatment of refractory metastatic disease.
In recent years, molecular targeted therapies for cancer have shown promise for many cancers. One key feature of targeted therapeutic approaches is reliable diagnostic and prognostic biomarkers. AXL has emerged as a new biomarker due to its role in biological processes and tumorigenesis. AXL belongs to the TAM family of receptor tyrosine kinases, including Tyro3 (or SKY), AXL and MER (O' Bryan, JR, molecular and Cellular Biology,5016-5031, 1991). The AXL receptor and its activating ligand growth arrest-specific protein 6 (GAS 6) are important drivers of metastasis and treatment resistance of human cancers. Overexpression and activation of the AXL-GAS6 signaling pathway has been found to be important in a wide variety of human tumors including kidney, pancreas, breast, lung, ovary and prostate cancers (rank, EK, PNAS,13373-13378,2014), and increased expression of AXL and GAS6 in tumors has historically been associated with poor prognosis and reduced survival rates, and with therapeutic resistance to conventional chemotherapeutic agents and targeted therapies.
Given the critical role that GAS6 and AXL play in advanced and refractory cancers, this signaling axis represents an attractive target for therapeutic intervention. AXL-targeted drugs, either as single agents or in combination with conventional chemotherapy or other small molecule inhibitors, have the potential to improve survival in many patients. Unfortunately, the exceptionally strong binding affinity of-30 pM between GAS6 and AXL makes the development of competitive antagonists challenging. AVB-500 is a therapeutic recombinant fusion protein that has been shown to neutralize GAS6 activity by binding GAS6 with very high affinity (see, e.g., PCT WO2019/090227, where AVB-500 is referred to as AVB-S6-500). In so doing, AVB-500 selectively inhibits the AXL-GAS6 signaling pathway, which is upregulated in more than one cancer type, including ovarian cancer. In preclinical studies, AXL-GAS6 inhibition has been shown to have anti-tumor activity in combination with a variety of anti-cancer therapies including radiation therapy, immune tumor agents, and chemotherapeutic agents that affect DNA replication and repair. AVB-500 is currently being evaluated in clinical studies and has been granted rapid audits for platinum-resistant recurrent ovarian cancer by The U.S. food and drug administration (The U.S. Food and Drug Administration) (FDA) (Fast Track Designation).
Patent document 13/554,954;13/595,936;13/714,875;13/950,111;14/712,731;14/650,852;14/650,854;14/910,565;16/761,246; US2011/022125; US2013/056435; US2012/069841; US2013/074809; US2013/074786; US2013/074796; all teachings of US2015/0315553 are expressly incorporated herein by reference.
Disclosure of the invention
The present invention is based in part on the surprising discovery that in platinum-resistant ovarian cancer studies, higher plasma soluble AXL/GAS6 ratios appear to correlate with responses to AXL decoy receptor (AXL decoy receptor) ("AVB-500"). Accordingly, the present invention provides diagnostic methods and biomarkers for pathological conditions such as cancer using AXL binding agents (AXL binding agents), such as AVB-500.
In one aspect, the invention provides a method of diagnosing and selecting a subject with cancer for treatment with an AXL binding agent, the method comprising: i) Detecting a level of sAXL activity in a biological sample from a subject; ii) detecting the level of soluble GAS6 activity in a biological sample from the subject; and iii) selecting the subject for treatment when the sAXL/GAS6 ratio is high. In various embodiments, the sAXL/GAS6 ratio is selected from the group consisting of: greater than 0.8, greater than 0.85, greater than 0.9, greater than 0.95, greater than 1.0, greater than 1.05, greater than 1.1, greater than 1.15, greater than 1.2, greater than 1.25, greater than 1.3, greater than 1.35, greater than 1.4, greater than 1.45, greater than 1.5, greater than 2.0, greater than 2.5, and greater than 3.0. In various embodiments, the AXL binding agent is a soluble AXL variant polypeptide.
In another aspect, the invention provides a method for treating or delaying progression of cancer in a subject having cancer, the method comprising administering to the subject a therapeutically effective amount of an AXL binding agent; wherein the sAXL/GAS6 ratio in the biological sample from the subject is high. In various embodiments, the sAXL/GAS6 ratio is selected from the group consisting of: greater than 0.8, greater than 0.85, greater than 0.9, greater than 0.95, greater than 1.0, greater than 1.05, greater than 1.1, greater than 1.15, greater than 1.2, greater than 1.25, greater than 1.3, greater than 1.35, greater than 1.4, greater than 1.45, greater than 1.5, greater than 2.0, greater than 2.5, and greater than 3.0. In various embodiments, the AXL binding agent is a soluble AXL variant polypeptide.
In another aspect, the invention provides a method of diagnosing and selecting a subject with cancer for treatment with an AXL binding agent, the method comprising: i) Detecting a level of sAXL phosphorylation in a biological sample from a subject; ii) detecting the level of GAS6 activity in a biological sample from the subject; and iii) selecting the subject for treatment with an AXL binding agent when the level of AXL phosphorylation and the level of soluble GAS6 are high. In various embodiments, the AXL phosphorylation marker is selected from the group consisting of: tyr698, tyr702, tyr703, tyr779, tyr821, tyr866, and Tyr929.
In some embodiments, the level of AXL activity is measured by AXL mRNA expression (AXL protein expression level). In some embodiments, the GAS6 activity level is measured by GAS6 mRNA expression level or GAS6 protein expression level. In some embodiments, the protein expression level is determined using a method selected from the group consisting of: immunohistochemistry (IHC), immunofluorescence, flow cytometry, and western blotting. In some embodiments, mRNA expression levels are determined using a method selected from the group consisting of: quantitative polymerase chain reaction (qPCR), reverse transcription qPCR (RT-qPCR), RNA sequencing, microarray analysis, in situ hybridization, and Serial Analysis of Gene Expression (SAGE).
In some embodiments, the biological sample is selected from the group consisting of: tissue samples, blood samples, serum samples, plasma samples, cerebrospinal fluid (CSF) samples, ascites fluid samples and cell culture samples.
In various embodiments, the cancer is selected from the group consisting of: b-cell lymphoma, lung cancer (small cell lung cancer and non-small cell lung cancer), bronchi cancer, colorectal cancer, prostate cancer, breast cancer, pancreatic cancer, gastric cancer, ovarian cancer, bladder cancer, brain or central nervous system cancer, peripheral nervous system cancer, esophageal cancer, cervical cancer, melanoma, uterine or endometrial cancer, cancer of the oral cavity or pharynx, liver cancer, kidney cancer, biliary tract cancer, small intestine or appendiceal cancer, salivary gland cancer, thyroid cancer, adrenal gland cancer, osteosarcoma, chondrosarcoma, liposarcoma, testicular cancer and malignant fibrous histiocytoma, skin cancer, head and neck cancer, lymphoma, sarcoma, multiple myeloma and leukemia. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is breast cancer.
In some embodiments, the cancer is a cancer that overexpresses the biomarker GAS6 and/or AXL. In some embodiments, the cancer is a recurrent cancer. In some embodiments, the cancer is a human metastatic cancer that is resistant to standard therapies. In some embodiments, the human metastatic cancer is a chemotherapy-resistant cancer. In some embodiments, the human metastatic cancer is a platinum-resistant cancer.
In various embodiments, the method for treating or delaying progression of cancer in a subject further comprises a second therapy selected from the group consisting of: small molecule kinase inhibitor targeted therapies, surgery, cytoreductive therapies, cytotoxic chemotherapy and immunotherapy. In various embodiments, the combination therapies will be synergistic. In some embodiments, the second therapy is cytoreductive therapy and the combination may increase the therapeutic index of the cytoreductive therapy. In some embodiments, cytoreductive therapies may play a role in the DNA repair pathway. In some embodiments, the cytoreductive therapy is radiation therapy. In some embodiments, the combination may be synergistic.
In some embodiments, the second therapy is a chemotherapeutic agent selected from the group consisting of: daunorubicin, doxorubicin, epirubicin, idarubicin, anamycin (anamycin), MEN 10755, etoposide, teniposide, vinca alkaloid, vincristine, vinorelbine (navlbine), vindesine, vindoline (vindoline), vincamine, mechlorethamine (mechlorethamine), cyclophosphamide, melphalan (L-lysosarcoma), carmustine (BCNU), lomustine (CCNU), semustine (methyl-CCNU), streptozotocin, chlorourea, cytarabine (CYTOSAR-U), cytosine arabinoside, fluorouracil (5-FU), fluorouridine (FUdR), thioguanine (6-thioguanine), mercaptopurine (6-MP), spinosamine, fluorouracil (5-FU), methotrexate, 10-propyl-5, 8-df, oxaliplatin (ddha), dydroxyfogline (ddha), cisplatin (ddha), dydroxyfop (ddha), dydroxyfop (d), and oxyfogliptin (ddha).
In some embodiments, the second therapy will comprise administration of a poly (ADP-ribose) polymerase (PARP) inhibitor. In some embodiments, the PARP inhibitor is selected from the group consisting of: ABT-767, AZD 2461, BGB-290, BGP 15, CEP 9722, E7016, E7449, fluxaparide, INO1001, JPI 289, MP 124, nilaparib, olaparide, ONO2231, rupa, SC 101914, taprazoparide, vitamin Li Pali, WW 46, or salts or derivatives thereof, olaparide, rupa, nilaparib, taprazoparide, and valiparib. In some embodiments, the combination may be synergistic.
In some embodiments, the method of treatment will comprise administering a combination of an AXL binding agent and polyethylene glycol liposomal doxorubicin (PLD). In some embodiments, the method of treatment will comprise administering a combination of an AXL binding agent and paclitaxel. In some embodiments, the combination may be synergistic.
In some embodiments, the second therapy will include an immunotherapy selected from, but not limited to: treatment with depleting antibodies against specific tumor antigens; treatment with antibody-drug conjugates; treatment with agonistic, antagonistic or blocking antibodies against co-stimulatory or co-inhibitory molecules (immune checkpoints) such as CTLA-4, PD-1, OX-40, CD137, GITR, LAG3, TIM-3 and VISTA; use of bispecific T cell engagement antibodies
Figure BDA0004131772340000061
Treatment such as blepharomab (blinatumomab); treatment involving administration of biological response modifiers such as IL-2, IL-12, IL-15, IL-21, GM-CSF, IFN- α, IFN- β, and IFN- γ; treatment with therapeutic vaccines such as sipuleucel-T; treatment with a dendritic cell vaccine or a tumor antigen peptide vaccine; treatment using Chimeric Antigen Receptor (CAR) -T cells; treatment with CAR-NK cells; treatment with Tumor Infiltrating Lymphocytes (TILs); treatment with adoptively transferred anti-tumor T cells (ex vivo expanded and/or TCR transgenic); treatment with TALL-104 cells; and treatment with immunostimulants such as Toll-like receptor (TLR) agonists CpG and imiquimod (imiquimod); wherein the combination therapy provides increased effector cell killing of tumor cells, i.e., there is a synergistic effect between the AXL binding agent and the immunotherapy when co-administered.
In some embodiments, the AXL binding agent is a soluble AXL polypeptide. In some embodiments, the soluble AXL polypeptide is a soluble AXL variant polypeptide, wherein the soluble AXL variant polypeptide lacks an AXL transmembrane domain, lacks a functional Fibronectin (FN) domain, has one or more Ig1 domains, has one or more Ig2 domains, and wherein the AXL variant polypeptide exhibits increased affinity for an AXL variant polypeptide to bind GAS6 as compared to wild-type AXL.
In some embodiments, the soluble AXL polypeptide is a soluble AXL variant polypeptide, wherein the soluble AXL variant polypeptide lacks an AXL transmembrane domain, lacks a functional Fibronectin (FN) domain, has one Ig1 domain, lacks a functional Ig2 domain, and wherein the AXL variant polypeptide exhibits increased affinity for binding GAS6 by the AXL variant polypeptide as compared to wild-type AXL.
In some embodiments, the AXL variant polypeptide is a fusion protein comprising an Fc domain. In some embodiments, the variant polypeptide lacks an AXL intracellular domain. In some embodiments, the soluble AXL variant polypeptide further lacks a functional Fibronectin (FN) domain, and wherein the variant polypeptide exhibits increased affinity for the polypeptide to bind GAS 6. In some embodiments, the soluble AXL variant polypeptide comprises at least one amino acid modification relative to the wild-type AXL sequence.
In some embodiments, the soluble AXL variant polypeptide comprises at least one amino acid modification located in a region selected from the group consisting of: 1) between positions 15-50 of the wild-type AXL sequence (SEQ ID NO: 1), 2) between positions 60-120 of the wild-type AXL sequence (SEQ ID NO: 1), and 3) between positions 125-135 of the wild-type AXL sequence (SEQ ID NO: 1).
In some embodiments, the soluble AXL variant polypeptide comprises at least one amino acid modification at the following positions in the wild-type AXL sequence (SEQ ID NO: 1): 19. 23, 26, 27, 32, 33, 38, 44, 61, 65, 72, 74, 78, 79, 86, 87, 88, 90, 92, 97, 98, 105, 109, 112, 113, 116, 118 or 127 or a combination thereof.
In some embodiments, the soluble AXL variant polypeptide comprises at least one amino acid modification selected from the group consisting of: 1) a19T, 2) T23M, 3) E26G, 4) E27G or E27K, 5) G32S, 6) N33S, 7) T38I, 8) T44A, 9) H61Y, 10) D65N, 11) a72V, 12) S74N, 13) Q78E, 14) V79M, 15) Q86R, 16) D87G, 17) D88N, 18) I90M or I90V, 19) V92A, V G or V92D, 20) I97R, 21) T98A or T98P, 22) T105M, 23) Q109R, 24) V38A, 25) F113L, 26) H116R, 27) T118A, 28) G127R or G127E and 29) G129E, and combinations thereof.
In some embodiments, the AXL variant polypeptide comprises amino acid changes relative to the wild-type AXL sequence (SEQ id no: 1) at positions: (a) glycine 32; (b) aspartic acid 87; (c) valine 92; and (d) glycine 127.
In some embodiments, the AXL variant polypeptide comprises amino acid changes relative to the wild-type AXL sequence (SEQ ID NO: 1) at positions: (a) aspartic acid 87 and (b) valine 92.
In some embodiments, the AXL variant polypeptide comprises amino acid changes relative to the wild-type AXL sequence (SEQ ID NO: 1) at positions: (a) glycine 32; (b) aspartic acid 87; (c) valine 92; (d) glycine 127 and (e) alanine 72.
In some embodiments, the AXL variant polypeptide comprises amino acid changes relative to the wild-type AXL sequence (SEQ ID NO: 1) at positions: alanine 72.
In some embodiments, the AXL variant polypeptide has a glycine 32 residue substituted with a serine residue, an aspartic acid 87 residue substituted with a glycine residue, a valine 92 residue substituted with an alanine residue, or a glycine 127 residue substituted with an arginine residue, or a combination thereof.
In some embodiments, the aspartic acid 87 residue of an AXL variant polypeptide residue is replaced with a glycine residue, or the valine 92 residue is replaced with an alanine residue, or a combination thereof.
In some embodiments, alanine 72 of the AXL variant polypeptide is substituted with a valine residue.
In some embodiments, the AXL variant polypeptide has a glycine 32 residue substituted with a serine residue, an aspartic acid 87 residue substituted with a glycine residue, a valine 92 residue substituted with an alanine residue, a glycine 127 residue substituted with an arginine residue, or an alanine 72 residue substituted with a valine residue, or a combination thereof.
In some embodiments, the AXL variant polypeptide comprises amino acid changes relative to the wild-type AXL sequence (SEQ ID NO: 1) at positions: (a) glutamic acid 26; (b) valine 79; (c) valine 92; and (d) glycine 127.
In some embodiments, the AXL variant polypeptide has the glutamic acid 26 residue replaced with a glycine residue, the valine 79 residue replaced with a methionine residue, the valine 92 residue replaced with an alanine residue, or the glycine 127 residue replaced with an arginine residue, or a combination thereof.
In some embodiments, the AXL variant polypeptide comprises at least one amino acid region selected from the group consisting of: amino acid regions 19-437, 130-437, 19-132, 21-121, 26-132, 26-121 and 1-437 of the wild-type AXL polypeptide (SEQ ID NO: 1), and wherein one or more amino acid modifications occur in said amino acid regions.
In some embodiments, the AXL variant polypeptide comprises amino acid changes relative to the wild-type AXL sequence (SEQ ID NO: 1) at positions: (a) glycine 32; (b) aspartic acid 87; (c) alanine 72 and valine 92.
In some embodiments, glycine 32 of the AXL variant polypeptide is substituted with a serine residue, aspartic acid 87 is substituted with a glycine residue, alanine 72 is substituted with a valine residue, and valine 92 is substituted with an alanine residue, or a combination thereof.
In some embodiments, the soluble AXL polypeptide is a fusion protein comprising an Fc domain, and wherein the AXL variant comprises amino acid changes relative to the wild-type AXL sequence (SEQ ID NO: 1) at positions: (a) glycine 32; (b) aspartic acid 87; (c) alanine 72; and (d) valine 92.
In some embodiments, the soluble AXL polypeptide is a fusion protein comprising an Fc domain, and wherein glycine 32 is substituted with a serine residue, aspartic acid 87 is substituted with a glycine residue, alanine 72 is substituted with a valine residue, and valine 92 is substituted with an alanine residue, or a combination thereof.
In some embodiments, the soluble AXL polypeptide is a fusion protein comprising an Fc domain, and wherein the AXL variant comprises amino acid changes relative to the wild-type AXL sequence (SEQ ID NO: 1) at positions: (a) glycine 32; (b) aspartic acid 87; (c) alanine 72; (d) valine 92; and (e) glycine 127.
In some embodiments, the soluble AXL polypeptide is a fusion protein comprising an Fc domain, and wherein glycine 32 is substituted with a serine residue, aspartic acid 87 is substituted with a glycine residue, alanine 72 is substituted with a valine residue, valine 92 is substituted with an alanine residue, and glycine 127 is substituted with an arginine residue, or a combination thereof.
In some embodiments, the soluble AXL polypeptide is a fusion protein comprising an Fc domain, lacking a functional FN domain, and wherein the AXL variant comprises amino acid changes relative to the wild-type AXL sequence (SEQ ID NO: 1) at positions: (a) glycine 32; (b) aspartic acid 87; (c) alanine 72; and (d) valine 92.
In some embodiments, the soluble AXL variant polypeptide is a fusion protein comprising an Fc domain, lacking a functional FN domain, and wherein glycine 32 is substituted with a serine residue, aspartic acid 87 is substituted with a glycine residue, alanine 72 is substituted with a valine residue, and valine 92 is substituted with an alanine residue, or a combination thereof.
In some embodiments, the soluble AXL polypeptide is a fusion protein comprising an Fc domain, lacking a functional FN domain, and wherein the AXL variant comprises amino acid changes relative to the wild-type AXL sequence (SEQ ID NO: 1) at positions: (a) glycine 32; (b) aspartic acid 87; (c) alanine 72; (d) valine 92; and (e) glycine 127.
In some embodiments, the soluble AXL variant polypeptide is a fusion protein comprising an Fc domain, lacking a functional FN domain, and wherein glycine 32 is substituted with a serine residue, aspartic acid 87 is substituted with a glycine residue, alanine 72 is substituted with a valine residue, valine 92 is substituted with an alanine residue, and glycine 127 is substituted with an arginine residue, or a combination thereof.
In some embodiments, the soluble AXL polypeptide is a fusion protein comprising an Fc domain, a functional FN domain, an Ig2 domain, and wherein the AXL variant comprises amino acid changes relative to the wild-type AXL sequence (SEQ ID NO: 1) at positions: (a) glycine 32; (b) aspartic acid 87; (c) alanine 72 and (d) valine 92.
In some embodiments, the soluble AXL variant polypeptide is a fusion protein comprising an Fc domain, a functional FN domain lacking, an Ig2 domain lacking, and wherein glycine 32 is substituted with a serine residue, aspartic acid 87 is substituted with a glycine residue, alanine 72 is substituted with a valine residue, and valine 92 is substituted with an alanine residue, or a combination thereof.
In some embodiments, the soluble AXL variant polypeptide is a fusion protein comprising an Fc domain, a functional FN domain lacking, an Ig2 domain lacking, and wherein the AXL variant comprises amino acid changes relative to the wild-type AXL sequence (SEQ ID NO: 1) at positions: (a) glycine 32; (b) aspartic acid 87; (c) alanine 72; (d) valine 92; and (e) glycine 127.
In some embodiments, the soluble AXL variant polypeptide is a fusion protein comprising an Fc domain, a functional FN domain lacking, an Ig2 domain lacking, and wherein glycine 32 is substituted with a serine residue, aspartic acid 87 is substituted with a glycine residue, alanine 72 is substituted with a valine residue, valine 92 is substituted with an alanine residue, and glycine 127 is substituted with an arginine residue, or a combination thereof.
In some embodiments, the soluble AXL binding agent is a fusion protein comprising the use of an AXL decoy receptor comprising a soluble AXL variant polypeptide comprising an amino acid change relative to the wild-type AXL sequence (SEQ ID NO: 1) at: (a) glycine 32; (b) aspartic acid 87; (c) alanine 72; (d) valine 92; and (e) glycine 127, lack AXL transmembrane domain, lack functional FN domain, and the fusion protein comprises an Fc domain (hereinafter AVB-500) linked to a soluble AXL variant polypeptide by a peptide linker.
In some embodiments, the soluble AXL variant polypeptide has at least about 1x10 for GAS6 -8 M、1x10 -9 M、1x10 -10 M、1x10 -11 M or 1x10 -12 Affinity of M.
In some embodiments, the soluble AXL variant polypeptide exhibits an affinity for GAS6 that is at least about 5-fold stronger, at least about 10-fold stronger, or at least about 20-fold stronger than the affinity of the wild-type AXL polypeptide.
In some embodiments, the soluble AXL variant polypeptide further comprises a linker. In some embodiments, the linker comprises one or more (GLY) 4 A SER unit. In some embodiments, the linker comprises 1, 2, 3, or 5 (GLY) 4 A SER unit.
In some embodiments, the dose of the soluble AXL variant polypeptide administered to the patient is selected from the group consisting of: about 0.5mg/kg, about 1.0mg/kg, about 1.5mg/kg, about 2.0mg/kg, about 2.5mg/kg, about 3.0mg/kg, about 3.5mg/kg, about 4.0mg/kg, about 4.5mg/kg, about 5.0mg/kg, about 5.5mg/kg, about 6.0mg/kg, about 6.5mg/kg, about 7.0mg/kg, about 7.5mg/kg, about 8.0mg/kg, about 8.5mg/kg, about 9.0mg/kg, about 9.5mg/kg, about 10.0mg/kg, about 10.5mg/kg, about 11.0mg/kg, about 11.5mg/kg, about 12.0mg/kg, about 12.5mg/kg, about 13.0mg/kg, about 13.5mg/kg, about 14.0mg/kg, about 14.5mg/kg, about 15.0mg/kg, about 16.5mg/kg, about 17.5mg/kg, about 16.5mg/kg, about 18.5 mg/kg. In some embodiments, the soluble AXL variant polypeptide will be administered as an IV infusion at a dose of 20mg/kg per week within 30 minutes or 60 minutes. In some embodiments, the soluble AXL variant polypeptide will be administered as an IV infusion at a dose of 15mg/kg per week within 30 minutes or 60 minutes. In some embodiments, the soluble AXL variant polypeptide will be administered as an IV infusion at a dose of 10mg/kg per week within 30 minutes or 60 minutes. In some embodiments, the soluble AXL variant polypeptide will be administered as an IV infusion at a dose of 5mg/kg per week within 30 minutes or 60 minutes. In some embodiments, the soluble AXL variant polypeptide will be administered as an IV infusion at a dose of 2.5mg/kg per week over 30 minutes or 60 minutes. In some embodiments, the soluble AXL variant polypeptide will be administered as an IV infusion at a dose of 1mg/kg per week within 30 minutes or 60 minutes. In some embodiments, the soluble AXL variant polypeptide will be administered as an IV infusion at a dose of 20mg/kg every 14 days within 30 minutes or 60 minutes. In some embodiments, the soluble AXL variant polypeptide will be administered as an IV infusion at a dose of 15mg/kg every 14 days within 30 minutes or 60 minutes. In some embodiments, the soluble AXL variant polypeptide will be administered as an IV infusion at a dose of 10mg/kg every 14 days within 30 minutes or 60 minutes. In some embodiments, the soluble AXL variant polypeptide will be administered as an IV infusion at a dose of 5mg/kg every 14 days within 30 minutes or 60 minutes. In some embodiments, the soluble AXL variant polypeptide will be administered as an IV infusion at a dose of 2.5mg/kg every 14 days within 30 minutes or 60 minutes. In some embodiments, the soluble AXL variant polypeptide will be administered as an IV infusion at a dose of 1mg/kg every 14 days within 30 minutes or 60 minutes.
Brief Description of Drawings
FIG. 1 is a scatter plot depicting PFS as a function of sAXL/GAS6 ratio.
FIG. 2 is a scatter plot depicting the correlation of baseline serum AXL/GAS6 ratio (left vertical axis) to clinical response ratio in AVB-500P1b platinum-resistant ovarian cancer (PROC) studies.
Fig. 3A and 3B are bar graphs depicting (a) the clinical response of AVB-500+pac in patients with <3 month platinum free interval and (B) the clinical response of chemotherapy in patients with <3 month platinum free interval.
Fig. 4A and 4B are bar graphs depicting (a) the clinical response of AVB-500+pac in the third and fourth lines and (B) the clinical response of chemotherapy in the third and fourth lines.
Mode for carrying out the invention
Unless defined otherwise herein, scientific and technical terms used in connection with the present invention shall have the meanings commonly understood by one of ordinary skill in the art. Furthermore, unless the context requires otherwise, singular terms shall include the plural and plural terms shall include the singular. In general, the nomenclature and techniques described herein for cell and tissue culture, molecular biology, immunology, microbiology, genetics, and protein and nucleic acid chemistry and hybridization are those commonly used and well known in the art. Unless otherwise indicated, the methods and techniques of the present invention are generally performed according to conventional methods well known in the art and described in various general and more specific references cited and discussed throughout the present specification. See, e.g., green and Sambrook, molecular Cloning: A Laboratory Manual,4th ed., cold Spring Harbor Laboratory Press, cold Spring Harbor, n.y. (2012), incorporated herein by reference. Enzymatic reactions and purification techniques are performed according to the manufacturer's instructions, as is commonly done in the art or as described herein. The nomenclature used and the experimental procedures and techniques described herein in connection with analytical chemistry, synthetic organic chemistry, and pharmaceutical chemistry are those commonly employed and well known in the art. Standard techniques are used for chemical synthesis, chemical analysis, drug preparation, formulation and delivery, and subject treatment.
The terms "polypeptide," "peptide," and "protein" are used interchangeably herein to refer to a polymer of two or more amino acid residues. These terms apply to amino acid polymers in which one or more amino acid residues are artificial chemical mimics of the corresponding naturally occurring amino acid, as well as naturally occurring amino acid polymers and non-naturally occurring amino acid polymers. The terms "antibody" and "antibodies" are used interchangeably herein and refer to a polypeptide capable of interacting with and/or binding to another molecule, commonly referred to as an antigen. Antibodies may include, for example, an "antigen binding polypeptide" or a "target molecule binding polypeptide". Antigens of the invention may include, for example, any of the polypeptides described herein.
The term "amino acid" refers to naturally occurring amino acids and synthetic amino acids, as well as amino acid analogs and amino acid mimics that function in a manner similar to naturally occurring amino acids. Naturally occurring amino acids are those encoded by the genetic code, as well as those amino acids that are later modified, for example, hydroxyproline, gamma-carboxyglutamic acid, and O-phosphoserine. Amino acid analogs refer to compounds that have the same basic chemical structure as a naturally occurring amino acid (i.e., an α -carbon is bound to hydrogen, a carboxyl group, an amino group, and an R group), e.g., homoserine, norleucine, methionine sulfoxide, methionine methyl sulfonium. Such analogs have modified R groups (e.g., norleucine) or modified peptide backbones, but retain the same basic chemical structure as a naturally occurring amino acid. Amino acid mimetics refers to compounds that have a structure that is different from the general chemical structure of an amino acid, but that function in a manner similar to naturally occurring amino acids. All single letters used in the present invention to represent amino acids are used according to accepted amino acid notations commonly used in the art, e.g., a means alanine, C means cysteine, and so on. Amino acids are indicated by single letters before and after the relevant position to reflect the change from the original amino acid (before the position) to the changed amino acid (after the position). For example, a19T means that the amino acid alanine at position 19 is changed to threonine.
The term "tumor", as used herein, refers to all neoplastic cell growth and proliferation (whether malignant or benign) as well as all pre-cancerous and cancerous cells and tissues. The terms "cancer", "cancerous", "cell proliferative disorder", "proliferative disorder" and "tumor" are not mutually exclusive when referred to herein.
The terms "cancer," "neoplasm," and "tumor" are used interchangeably herein to refer to cells that exhibit autonomous, unregulated growth such that they exhibit an abnormal growth phenotype characterized by a substantial loss of control over cell proliferation. In general, cells of interest to be detected, analyzed, classified, or treated in this application include pre-cancerous (e.g., benign) cells, malignant cells, pre-metastatic cells, and non-metastatic cells.
The term "primary tumor" refers to all neoplastic cell growth and proliferation (whether malignant or benign) and all pre-cancerous and cancerous cells and tissues located at anatomical sites where spontaneous, deregulated growth of cells begins (e.g., organs of the original cancerous tumor). Primary tumors do not include metastasis.
The "pathology" of cancer includes all phenomena that impair the health of a patient. This includes, but is not limited to, abnormal or uncontrolled cell growth, primary tumor growth and formation, metastasis, interference with normal function of neighboring cells, release of cytokines or other secretory products at abnormal levels, suppression or exacerbation of inflammatory or immune responses, neoplasia, precancerous lesions, malignant tumors, invasion of surrounding or distant tissues or organs such as lymph nodes, and the like.
As used herein, the terms "cancer recurrence" and "tumor recurrence" and grammatical variants thereof refer to the further growth of neoplastic or cancerous cells following the diagnosis of cancer. In particular, recurrence may occur when further cancerous cell growth occurs in cancerous tissue. Similarly, "tumor spread" occurs when tumor cells spread into local or distant tissues and organs; thus, tumor spread includes tumor metastasis. "tumor invasion" occurs when tumor growth spreads locally to impair the function of the tissue involved by compressing, destroying or preventing normal organ function.
As used herein, the term "metastasis" refers to the growth of a cancerous tumor in an organ or body part that is not directly connected to the organ of the original cancerous tumor. Metastasis will be understood to include micrometastases, which are the presence of undetectable amounts of cancerous cells in an organ or body part that is not directly connected to an organ of the original cancerous tumor (e.g., an organ containing the primary tumor). Metastasis can also be defined as several steps of a process, such as the departure of cancer cells from the original tumor site (e.g., the primary tumor site), and migration and/or invasion of cancer cells to other parts of the body.
Depending on the nature of the cancer, appropriate patient samples are obtained. As used herein, the phrase "cancerous tissue sample" refers to any cell obtained from a cancerous tumor. In the case of solid tumors that have not metastasized (e.g., primary tumors), tissue samples are typically obtained from surgically removed tumors and are ready to be tested by conventional techniques.
"early stage cancer" or "early stage tumor" means a non-invasive or metastatic cancer, or a cancer classified as stage 0, stage 1 or stage 2. Examples of cancers include, but are not limited to, epithelial cancers, lymphomas, blastomas (including medulloblastomas and retinoblastomas), sarcomas (including liposarcomas and synovial cell sarcomas), neuroendocrine tumors (including carcinoid tumors, gastrinomas, and islet cell carcinomas), mesothelioma, schwannoma (including auditory neuroma), meningioma, adenocarcinoma, melanoma, and leukemia or lymphoid malignancies. More specific examples of such cancers include bladder cancer (e.g., transitional cell carcinoma or urothelial carcinoma, non-myogenic invasive bladder carcinoma, myogenic invasive bladder carcinoma and metastatic bladder carcinoma) and non-urothelial bladder carcinoma), squamous cell carcinoma (e.g., epithelial squamous cell carcinoma), lung cancer including small-cell lung carcinoma (SCLC), non-small-cell lung carcinoma (NSCLC), adenocarcinoma of the lung and squamous carcinoma of the lung, peritoneal carcinoma, hepatocellular carcinoma, gastric (gastric) carcinoma or gastric (stomach) carcinoma including gastrointestinal carcinoma, pancreatic carcinoma, glioblastoma, cervical carcinoma, ovarian carcinoma, liver carcinoma, hepatoma, breast carcinoma (including metastatic breast carcinoma), colon carcinoma, rectal carcinoma, colorectal carcinoma, endometrial carcinoma or uterine epithelial carcinoma, salivary gland epithelial carcinoma, kidney carcinoma or renal carcinoma, prostate carcinoma, vulval carcinoma, thyroid carcinoma, hepatic epithelial carcinoma, anal epithelial carcinoma, penile carcinoma, merkel cell carcinoma, mycosis, cancer, biliary tract carcinoma, head and neck carcinoma, and hematological carcinoma.
Tumors of interest treated with the methods of the invention include solid tumors, such as, for example, cancers of the epidermis, gliomas, melanomas, sarcomas, and the like. Of particular interest are ovarian and breast cancers. Epithelial cancers include a variety of adenocarcinomas, such as those in the prostate, lung, etc.; adrenal cortex epithelial cancer; hepatocellular carcinoma; renal cell epithelial cancer, ovarian epithelial cancer, in situ epithelial cancer, ductal epithelial cancer, breast epithelial cancer, basal cell epithelial cancer; squamous cell epithelial cancer; transitional cell epithelial cancer; colon epithelial cancer; nasopharyngeal epithelial cancer; multiple atrial cystic kidney cell epithelial cancer; oat cell epithelial cancer, large cell lung epithelial cancer; small cell lung epithelial cancer, and the like. Epithelial cancers can be found in the prostate, pancreas, colon, brain (e.g., glioblastoma), lung, breast, skin, and the like. Included among the names soft tissue tumors are neoplasms derived from fibroblasts, myofibroblasts, histiocytes, vascular/endothelial cells and schwann cells. Tumors of connective tissue include sarcomas; histiocytoma; fibroids; osteosarcoma; extraosseous mucoid chondrosarcoma; clear cell sarcoma; fibrosarcoma, and the like. Hematological cancers include leukemias and lymphomas, such as cutaneous T cell lymphomas, acute Myelogenous Leukemia (AML), chronic Myelogenous Leukemia (CML), acute Lymphoblastic Leukemia (ALL), non-hodgkin's lymphoma (NHL), and the like. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is a cancer that overexpresses the biomarker GAS6 and/or AXL. In some embodiments, the patient previously responded to treatment with the anti-cancer therapy, but suffered from a relapse (hereinafter "recurrent cancer") after cessation of the therapy. In some embodiments, the cancer is resistant to standard therapies. In some embodiments, the cancer is a chemotherapy-resistant cancer. In some embodiments, the cancer is a platinum-resistant cancer.
"tumor immunity" refers to the process by which tumors evade immune recognition and clearance. Thus, as a therapeutic concept, when such evasion is attenuated, tumor immunity is "treated" and the tumor is recognized and attacked by the immune system. Examples of tumor recognition include tumor binding, tumor shrinkage, and tumor elimination.
The term "sample" as used herein refers to a composition obtained or derived from a subject and/or individual of interest that includes cells and/or other molecular entities characterized and/or identified, for example, based on physical, biochemical, chemical, and/or physiological characteristics. For example, the phrase "disease sample" and variations thereof refers to any sample obtained from a subject of interest that is expected or known to contain the cell and/or molecular entity to be characterized. Samples include, but are not limited to, tissue samples, primary or cultured cells or cell lines, cell supernatants, cell lysates, platelets, serum, plasma, vitreous humor, lymph, synovial fluid, follicular fluid, semen, amniotic fluid, milk, whole blood, blood derived cells, urine, cerebrospinal fluid, saliva, sputum, tears, sweat, mucus, tumor lysates and tissue culture media, tissue extracts such as homogenized tissue, tumor tissue, cell extracts, and combinations thereof.
"tissue sample" or "cell sample" means a collection of similar cells obtained from the tissue of a subject or individual. The source of the tissue or cell sample may be solid tissue from fresh, frozen and/or preserved organs, tissue samples, biopsies and/or aspirates; blood or any blood component, such as plasma; body fluids such as cerebrospinal fluid, amniotic fluid, peritoneal fluid or interstitial fluid; cells from any time during gestation or development in a subject. The tissue sample may also be a primary or cultured cell or cell line. Optionally, the tissue or cell sample is obtained from a diseased tissue/organ. For example, a "tumor sample" is a tissue sample obtained from a tumor or other cancerous tissue. The tissue sample may comprise a mixed population of cell types (e.g., tumor cells and non-tumor cells, cancer cells and non-cancer cells). The tissue sample may contain compounds that do not naturally mix with each other with tissue in nature, such as preservatives, anticoagulants, buffers, fixatives, nutrients, antibiotics, or the like.
The term "detection" includes any means of detection, including direct and indirect detection.
The term "biomarker" as used herein refers to an indicator, such as a predictive, diagnostic, and/or prognostic indicator, that can be detected in a sample. Biomarkers can be used as indicators of specific subtypes of a disease or disorder (e.g., cancer) characterized by certain molecular, pathological, histological, and/or clinical features. In some embodiments, the biomarker is a gene. Biomarkers include, but are not limited to, polynucleotides (e.g., DNA and/or RNA), alterations in polynucleotide copy number (e.g., DNA copy number), polypeptides, polypeptide modifications and polynucleotide modifications (e.g., post-translational modifications), carbohydrates (carbohydrates), and/or glycolipid-based molecular markers.
As used herein, when the biomarkers AXL and GAS6 are evaluated, the AXL/GAS6 ratio is defined as "high" when the ratio is greater than 0.8.
"sustained response" refers to a sustained effect on reducing tumor growth after cessation of treatment. For example, the tumor size may remain the same or smaller than the size at the beginning of the administration phase. In some embodiments, the sustained response has a duration at least the same as the duration of the treatment, at least 1.5 times, 2.0 times, 2.5 times, or 3.0 times the length of the duration of the treatment.
As used herein, "reducing or inhibiting cancer recurrence" means reducing or inhibiting tumor or cancer recurrence or tumor or cancer progression. As disclosed herein, cancer recurrence and/or cancer progression include, but are not limited to, cancer metastasis.
As used herein, "complete response" or "CR" refers to the disappearance of all target lesions.
As used herein, "partial response" or "PR" refers to a reduction in SLD of a target lesion of at least 30% with reference to the sum of the longest diameters of the baselines (SLD).
As used herein, "stable disease" or "SD" refers to a target lesion that is neither contracted enough to conform to PR nor increased enough to conform to PD, with reference to the smallest SLD since the initiation of treatment.
As used herein, "progressive disease" or "PD" refers to an increase in SLD of a target lesion by at least 20% or the presence of one or more new lesions with reference to the minimum SLD recorded since the initiation of treatment.
As used herein, "progression free survival" (PFS) refers to the length of time during which the disease (e.g., cancer) being treated does not worsen during and after treatment. Progression free survival may include the amount of time a patient experiences a complete response or a partial response, as well as the amount of time a patient experiences a stable disease.
As used herein, "overall response rate" or "objective response rate" (ORR) refers to the sum of the Complete Response (CR) rate and the Partial Response (PR) rate.
As used herein, "total survival" (OS) refers to the percentage of individuals in a group that are likely to be alive after a particular duration.
"inhibitors", "activators" and "modulators" of AXL or its ligand GAS6 ("AXL binding agent") are used to refer to inhibitory, activating or modulating molecules, e.g., ligands, receptors, agonists, antagonists and homologs and mimics thereof, respectively, identified using in vitro and in vivo assays for receptor or ligand binding or signaling.
The AXL binding agent having the desired pharmacological activity may be administered to a host in a physiologically acceptable carrier to modulate AXL/GAS6 function. The therapeutic agent may be administered in a variety of ways (oral, topical, parenteral, e.g., intravenous, subcutaneous, intraperitoneal, by viral infection, intravascular, etc.). Intravenous delivery is of particular interest. The compounds may be formulated in various ways depending on the manner of introduction. The concentration of the therapeutically active compound in the formulation may vary from about 0.1wt.% to 100 wt.%.
Pharmaceutical compositions may be prepared in various forms such as granules, tablets, pills, suppositories, capsules, suspensions, ointments, lotions and the like. Pharmaceutical grade organic or inorganic carriers and/or diluents suitable for oral and topical use can be used to make compositions containing the therapeutically active compounds. Diluents known in the art include aqueous media, vegetable and animal oils and fats. Stabilizers, wetting agents and emulsifiers, salts for varying the osmotic pressure or buffers for ensuring a proper pH value and skin penetration enhancers may be used as adjuvants.
By "pharmaceutically acceptable excipient" is meant an excipient that is generally safe, non-toxic and desirable for use in preparing a pharmaceutical composition, and includes excipients acceptable for veterinary use as well as for human pharmaceutical use. Such excipients may be solid, liquid, semi-solid, or, in the case of aerosol compositions, gaseous.
The terms "pharmaceutically acceptable", "physiologically tolerable" and grammatical variations thereof are used interchangeably in reference to compositions, carriers, diluents and reagents and mean that the substances are capable of or are administered to humans without producing undesirable physiological effects to an extent that would interfere with the administration of the compositions.
"dosage unit" refers to physically discrete units suitable as unitary dosages for the particular subject to be treated. Each unit may contain a predetermined amount of the active compound associated with the desired pharmaceutical carrier calculated to produce the desired therapeutic effect. The specification of the dosage unit form may be determined by: (a) The unique characteristics of the active compounds and the particular therapeutic effect to be achieved, and (b) limitations inherent in the technology of forming such active compounds.
The terms "subject," "individual," and "patient" are used interchangeably herein to refer to a mammal being evaluated for treatment and/or being treated. In embodiments, the mammal is a human. The terms "subject," "individual," and "patient" thus include individuals having cancer, including those who have undergone resection (surgery) to remove cancerous tissue or candidates to undergo resection (surgery) to remove cancerous tissue, including but not limited to adenocarcinoma of the ovary or prostate, breast cancer, glioblastoma, and the like. The subject may be a human, but also includes other mammals, particularly those that may be used as laboratory models of human disease, such as mice, rats, and the like.
The term "diagnosis" is used herein to refer to the identification of a molecular or pathological state, disease or condition, such as the identification of a viral infection.
As used herein, the terms "treatment", "treatment" and the like refer to the administration of an agent or procedure for the purpose of achieving an effect. The effect may be prophylactic in terms of completely or partially preventing a disease or symptom thereof, and/or may be therapeutic in terms of achieving a partial or complete cure of the disease and/or symptom of the disease. As used herein, "treatment" encompasses any treatment of any viral infection or exposure to a mammal, particularly a human, and includes: (a) preventing infection; (b) inhibiting the infection, i.e., preventing its development; and (c) alleviating the disease, i.e., causing the infection to resolve.
Treatment may refer to any indication of success in treating or ameliorating or preventing cancer, including any objective or subjective parameter, such as reduction, alleviation, diminishment of symptoms, or making a disease condition more tolerable to the subject; slowing the rate of degeneration or decay; or the end point of the degeneration is made less debilitating. Treatment or amelioration of symptoms can be based on objective or subjective parameters; including the results of physician examination. Accordingly, the term "treating" includes administration of a compound or agent of the invention to prevent or delay, alleviate or prevent or inhibit the development of symptoms or conditions. The term "therapeutic effect" refers to reducing, eliminating or preventing a disease, symptom of a disease, or side effect of a disease in a subject.
"therapeutically effective amount" refers to an amount of a compound that, when administered to a subject to treat breast or ovarian cancer, is sufficient to affect such treatment of cancer. The "therapeutically effective amount" may vary depending on, for example, the soluble AXL variant polypeptide selected, the stage of the cancer, the age, weight and/or health of the patient, and the discretion of the prescribing physician. The appropriate amount in any particular case can be readily determined by one skilled in the art, or can be determined by routine experimentation.
The phrase "determining the efficacy of a treatment" and variations thereof may include any method for determining that a treatment provides a benefit to a subject. The term "therapeutic efficacy" and variations thereof is generally expressed in terms of alleviation of one or more signs or symptoms associated with a disease and can be readily determined by one of ordinary skill in the art. "therapeutic efficacy" may also refer to the prevention or amelioration of signs and symptoms of toxicity normally associated with standard or nonstandard treatment of disease. The determination of the efficacy of a treatment is generally indication and disease specific and may include any method known or available in the art for determining that a treatment provides a beneficial effect to a patient. For example, evidence of therapeutic efficacy may include, but is not limited to, alleviation of a disease or indication. In addition, the therapeutic efficacy may also include an overall improvement in the overall health of the subject, such as, but not limited to, an increase in the quality of life of the patient, a predicted increase in the survival rate of the subject, a decrease in depression, or a decrease in the recurrence rate of the indication (increase in the time to remission). (see, e.g., physics' Desk Reference (2010)).
In the case of cancer or tumor, an effective amount of the drug may have the following effects: reducing the number of cancer cells; reducing tumor size; inhibit (i.e., slow or desirably stop to some extent) infiltration of cancer cells into peripheral organs; inhibit (i.e., slow down to some extent and desirably stop) tumor metastasis; inhibit tumor growth to some extent; and/or to some extent, alleviate one or more symptoms associated with the disorder. The effective amount may be administered in one or more administrations. For the purposes of the present invention, an effective amount of a drug, compound or pharmaceutical composition is an amount sufficient to accomplish prophylactic or therapeutic treatment, either directly or indirectly. As understood in the clinical context, an effective amount of a drug, compound, or pharmaceutical composition may be obtained in combination with another drug, compound, or pharmaceutical composition, or may be obtained without combination. Thus, an "effective amount" may be considered in the context of administration of one or more therapeutic agents, and a single agent may be considered to be administered in an effective amount if, in combination with one or more other agents, the desired result may or has been achieved.
As used herein, "in combination with" means that one mode of treatment is administered in addition to another mode of treatment. Thus, "in combination with" means that one mode of treatment is administered to an individual before, during, or after another mode of treatment.
In certain embodiments, "combined with" means that the first therapeutic agent and the compound as used herein are administered to the patient simultaneously. In some embodiments, the combination product is not administered simultaneously. When administered in combination, each component may be administered at the same time or sequentially in any order at different time points. Thus, each component may be administered alone, but close enough in time to provide the desired therapeutic effect.
By "concomitant administration" of a known cancer therapeutic agent with the pharmaceutical composition of the invention is meant that the agent and AXL variant are administered at a time when both the known agent and the composition of the invention have therapeutic effects. Such concomitant administration may include administration of the drug simultaneously (i.e., at the same time), prior to, or subsequent to administration of the compound of the invention. One of ordinary skill in the art will readily determine the appropriate timing, order, and dosage of administration of a particular drug and the compositions of the present invention.
As used herein, the term "correlation" or "correlation with" and similar terms refer to a statistical association between instances of two events, where an event includes a number, a dataset, and the like. For example, when an event involves numbers, positive correlation (also referred to herein as "direct correlation") means that as one number increases, the other number also increases. Negative correlation (also referred to herein as "inverse correlation") means that as one number increases, the other number decreases.
Exemplary embodiments
In one aspect, the invention provides a method of diagnosing and selecting a subject with cancer for treatment with an AXL binding agent, the method comprising: i) Detecting a level of sAXL activity in a biological sample from a subject; ii) detecting the level of soluble GAS6 activity in a biological sample from the subject; and iii) selecting the subject for treatment when the sAXL/GAS6 ratio is high. In various embodiments, the sAXL/GAS6 ratio is selected from the group consisting of: greater than 0.8, greater than 0.85, greater than 0.9, greater than 0.95, greater than 1.0, greater than 1.05, greater than 1.1, greater than 1.15, greater than 1.2, greater than 1.25, greater than 1.3, greater than 1.35, greater than 1.4, greater than 1.45, greater than 1.5, greater than 2.0, greater than 2.5, and greater than 3.0. In various embodiments, the AXL binding agent is an AXL variant polypeptide (also referred to as an "AXL decoy receptor"). In some embodiments, the soluble AXL binding agent is a fusion protein comprising the use of an AXL decoy receptor comprising a soluble AXL variant polypeptide comprising an amino acid change relative to the wild-type AXL sequence (SEQ ID NO: 1) at: (a) glycine 32; (b) aspartic acid 87; (c) alanine 72; (d) valine 92; and (e) glycine 127, lack AXL transmembrane domain, lack functional FN domain, and the fusion protein comprises an Fc domain (hereinafter AVB-500) linked to a soluble AXL variant polypeptide by a peptide linker (SEQ ID NO: 2).
In another aspect, the invention provides a method for treating or delaying progression of cancer in a subject having cancer, comprising administering to the subject a therapeutically effective amount of an AXL binding agent; wherein the sAXL/GAS6 ratio in the biological sample from the subject is high. In various embodiments, the sAXL/GAS6 ratio is selected from the group consisting of: greater than 0.8, greater than 0.85, greater than 0.9, greater than 0.95, greater than 1.0, greater than 1.05, greater than 1.1, greater than 1.15, greater than 1.2, greater than 1.25, greater than 1.3, greater than 1.35, greater than 1.4, greater than 1.45, greater than 1.5, greater than 2.0, greater than 2.5, and greater than 3.0. In various embodiments, the AXL binding agent is an AXL variant polypeptide (also referred to as an "AXL decoy receptor"). In some embodiments, the soluble AXL binding agent is a fusion protein comprising the use of an AXL decoy receptor comprising a soluble AXL variant polypeptide comprising an amino acid change relative to the wild-type AXL sequence (SEQ ID NO: 1) at: (a) glycine 32; (b) aspartic acid 87; (c) alanine 72; (d) valine 92; and (e) glycine 127, lack AXL transmembrane domain, lack functional FN domain, and the fusion protein comprises an Fc domain (e.g., AVB-500) linked to a soluble AXL variant polypeptide by a peptide linker.
In another aspect, the invention provides a method of diagnosing and selecting a subject with cancer for treatment with an AXL binding agent, the method comprising: i) Detecting a level of sAXL phosphorylation in a biological sample from a subject; ii) detecting the level of GAS6 activity in a biological sample from the subject; and iii) selecting the subject for treatment with an AXL binding agent when the level of AXL phosphorylation and the level of soluble GAS6 are high. In various embodiments, the AXL phosphorylation marker is selected from the group consisting of: tyr698, tyr702, tyr703, tyr779, tyr821, tyr866, and Tyr929. In various embodiments, the sAXL/GAS6 ratio is selected from the group consisting of: greater than 0.8, greater than 0.85, greater than 0.9, greater than 0.95, greater than 1.0, greater than 1.05, greater than 1.1, greater than 1.15, greater than 1.2, greater than 1.25, greater than 1.3, greater than 1.35, greater than 1.4, greater than 1.45, greater than 1.5, greater than 2.0, greater than 2.5, and greater than 3.0. In various embodiments, the AXL binding agent is an AXL variant polypeptide (also referred to as an "AXL decoy receptor"). In some embodiments, the soluble AXL binding agent is a fusion protein comprising the use of an AXL decoy receptor comprising a soluble AXL variant polypeptide comprising an amino acid change relative to the wild-type AXL sequence (SEQ ID NO: 1) at: (a) glycine 32; (b) aspartic acid 87; (c) alanine 72; (d) valine 92; and (e) glycine 127, lack AXL transmembrane domain, lack functional FN domain, and the fusion protein comprises an Fc domain (e.g., AVB-500) linked to a soluble AXL variant polypeptide by a peptide linker.
In various embodiments, the cancer is selected from the group consisting of: b-cell lymphoma, lung cancer (small cell lung cancer and non-small cell lung cancer), bronchi cancer, colorectal cancer, prostate cancer, breast cancer, pancreatic cancer, gastric cancer, ovarian cancer, bladder cancer, brain or central nervous system cancer, peripheral nervous system cancer, esophageal cancer, cervical cancer, melanoma, uterine or endometrial cancer, cancer of the oral cavity or pharynx, liver cancer, kidney cancer, biliary tract cancer, small intestine or appendiceal cancer, salivary gland cancer, thyroid cancer, adrenal gland cancer, osteosarcoma, chondrosarcoma, liposarcoma, testicular cancer and malignant fibrous histiocytoma, skin cancer, head and neck cancer, lymphoma, sarcoma, multiple myeloma and leukemia.
In some embodiments, the cancer is a cancer that overexpresses the biomarker GAS6 and/or AXL. In some embodiments, the cancer is a recurrent cancer. In some embodiments, the cancer is a human metastatic cancer that is resistant to standard therapies. In some embodiments, the human metastatic cancer is a chemotherapy-resistant cancer. In some embodiments, the human metastatic cancer is a platinum-resistant cancer.
In various embodiments, the method for treating or delaying progression of cancer in a subject further comprises a second therapy selected from the group consisting of: small molecule kinase inhibitor targeted therapies, surgery, cytoreductive therapies, cytotoxic chemotherapy and immunotherapy. In various embodiments, the combination therapy will be synergistic. In some embodiments, the second therapy is cytoreductive therapy and the combination may increase the therapeutic index of the cytoreductive therapy. In some embodiments, cytoreductive therapies may play a role in the DNA repair pathway. In some embodiments, the cytoreductive therapy is radiation therapy. In some embodiments, the combination may be synergistic.
In some embodimentsIn combination therapy includes antiproliferative or cytoreductive therapies. Antiproliferative or cytoreductive therapies are used therapeutically to eliminate tumor cells and other undesirable cells of a host, and include therapies such as delivering ionizing radiation and administering chemotherapeutic agents. For example, ionizing Radiation (IR) is used to damage or destroy cells by depositing energy in the treated area for treatment of about 60% of cancer patients, and for the purposes of the present invention may be delivered in conventional dosages and regimens or in reduced dosages. Radiation is nonspecific to cell damage and has a complex effect on DNA. The efficacy of treatment depends on the cellular damage to cancer cells being greater than to normal cells. Radiation therapy can be used to treat a variety of cancers. Some types of radiation therapy include photons, such as X-rays or gamma rays. Another technique for delivering radiation to cancer cells is internal radiotherapy, which places the radioactive implant directly in the tumor or body cavity so that the radiation dose is concentrated in a small area. Suitable doses of ionizing radiation may range from at least about 2Gy to no more than about 10Gy, typically about 5Gy. Suitable doses of ultraviolet radiation may range from at least about 5J/m 2 Up to about 50J/m 2 Typically about 10J/m 2 . The sample may be collected at least about 4 hours and not more than about 72 hours, typically about 4 hours or so, after uv irradiation.
Chemotherapeutic agents are well known in the art and are used at conventional dosages and schedules, or at reduced dosages or schedules, including, for example, topoisomerase inhibitors such as anthracyclines, including the compounds daunorubicin, doxorubicin (doxorubicin), epirubicin, idarubicin, enramycin, MEN 10755, and the like. Other topoisomerase inhibitors include etoposide and teniposide, which are podophyllotoxin analogs, and anthracenedione mitoxantrone and amsacrine. Other antiproliferative agents interfere with microtubule assembly, such as the vinca alkaloid family. Examples of vinca alkaloids include vinblastine, vincristine, vinorelbine (navlbine), vindesine, vindoline, vincamine, and the like. DNA damaging agents include nucleotide analogs, alkylating agents, and the like. Alkylating agents include nitrogen mustards (nitrogen mustards), e.g. mechlorethamine,Cyclophosphamide, melphalan (L-lysosarcosine), and the like; and nitrosoureas such as carmustine (BCNU), lomustine (CCNU), chromatemustine (methyl-CCNU), streptozotocin, chlorourein, and the like. Nucleotide analogs include pyrimidines such as cytoside (CYTOSAR-U), cytosine arabinoside, fluorouracil (5-FU), fluorouridine (FUdR), and the like; purines such as thioguanine (6-thioguanine), mercaptopurine (6-MP), prastatin, fluorouracil (5-FU), etc.; and folic acid analogs such as methotrexate, 10-propargyl-5, 8-deazafolic acid (PDDF, CB 3717), 5, 8-deazatetrahydrofolic acid (DDATHF), leucovorin, and the like. Other chemotherapeutic agents of interest include metal complexes such as cisplatin (cis-DDP), carboplatin, oxaliplatin, and the like; ureas, such as hydroxyurea; gemcitabine and hydrazines, such as N-methylhydrazine. In various embodiments, the dosage of such chemotherapeutic agents includes, but is not limited to, about 10mg/m 2 、20mg/m 2 、30mg/m 2 、40mg/m 2 、50mg/m 2 、60mg/m 2 、75mg/m 2 、80mg/m 2 、90mg/m 2 、100mg/m 2 、120mg/m 2 、150mg/m 2 、175mg/m 2 、200mg/m 2 、210mg/m 2 、220mg/m 2 、230mg/m 2 、240mg/m 2 、250mg/m 2 、260mg/m 2 And 300mg/m 2 Any one of them.
In some embodiments, the combination therapy will include immunotherapy. As used herein, the term "immunotherapy" refers to cancer treatment that includes, but is not limited to, the following: treatment with depleting antibodies against specific tumor antigens (see, e.g., blattman and Greenberg, science,305:200,2004; adams and Weiner, nat Biotech,23:1147,2005; vogal et al J Clin Oncology,20:719,2002; reviews by Colombat et al, blood,97:101, 2001); treatment with Antibody-Drug conjugates (see, e.g., ducry, laurent (eds.) anti Drug conjugates, in: methods in Molecular biology, book 1045.New York (NY), humana Press,2013;Nature Reviews Drug Discovery 12,259-260,2013, month 4); the use of a co-stimulatory or co-inhibitory molecule (immunoassay) directed against a polypeptide such asCheck point), agonistic, antagonistic, or blocking antibodies: CTLA-4 (ipilimumab)), PD-1 (na Wu Shankang, pamtirizumab (pembrolizumab), pidotizumab (pidilizumab)) and PD-L1 (BMS-936559, MPLD3280A, MEDI4736, MSB 0010718C) (see, e.g., philips and Atkins, international Immunology,27 (1); 39-46,2014, month 10), OX-40, CD137, GITR, LAG3, TIM-3 and VISTA (see, e.g., sharp et al, chin jcaner, 33 (9): 434-444, month 2014; hodi et al, N Engl J, 2010; topalian et al, N Engl J Med,366:2443-54,2012); use of bispecific T cell engagement antibodies
Figure BDA0004131772340000251
Such as treatment with bordetention (see, e.g., U.S. patent No. 9,260,522; U.S. patent application No. 20140302037); treatments involving the administration of biological response modifiers such as IL-2, IL-12, IL-15, IL-21, GM-CSF, IFN- α, IFN- β, and IFN- γ (see, e.g., sutlu T et al, journ of Internal Medicine,266 (2): 154-181,2009;Joshi S PNAS USA,106 (29): 12097-12102,2009; li Y et al, journal of Translational Medicine,7:11, 2009); treatment with therapeutic vaccines such as sipuleucel-T (see, e.g., kantoff PW New England Journal of Medicine,363 (5): 411-422,2010;Schlom J, journal of the National Cancer Institutes,104 (8): 599-613, 2012); treatment with a dendritic cell vaccine or a tumor antigen peptide vaccine; treatment using Chimeric Antigen Receptor (CAR) -T cells (see, e.g., rosenberg SA Nature Reviews Cancer,8 (4): 299-308,2008;Porter DL et al, new England Journal of Medicine,365 (8): 725-733,2011;Grupp SA et al, new England Journal of Medicine,368 (16): 1509-151,2013; U.S. patent No. 9,102,761; U.S. patent No. 9,101,584); treatment with CAR-NK cells (see, e.g., glinke et al, front Pharmacol,6 (21): 1-7,2015, 2 months); treatment using tumor-infiltrating lymphocytes (TILs) (see, e.g., wu et al, cancer j.,18 (2): 160-175, 2012); treatment using adoptively transferred anti-tumor T cells (ex vivo expanded and/or TCR transgenic) (see, e.g., wrzesinski et al, J Immunother,33 (1): 1-7, 2010); using TALL- 104 treatment of cells; and treatment with immunostimulants such as Toll-like receptor (TLR) agonists CpG and imiquimod (see, e.g., krieg, oncogene,27:161-167,2008;Lu,Front Immunol,5 (83): 1-4,2014, 3 months).
Immunotherapy focusing on the use of depleting antibodies against specific tumor antigens has been explored very successfully (see, e.g., blattman and Greenberg, science,305:200,2004; reviews of Adams and Weiner, nat Biotech,23:1147, 2005). Several examples of such tumor antigen specific depleting antibodies are
Figure BDA0004131772340000261
(anti-Her 2/neu mAb) (Baselga et al, J Clin Oncology, vol 14:737,1996; baselga et al, cancer Research,58:2825,1998; shak, semin. Oncology,26 (Suppl 12): 71,1999; vogal et al JClin Oncology,20:719, 2002); and->
Figure BDA0004131772340000262
(anti-CD 20 mAb) (Colombat et al, blood,97:101, 2001). Unfortunately, while clearly they have achieved significant success in tumor treatment, as monotherapy they are generally only effective in about 30% of individuals and only partially responsive. Furthermore, many individuals eventually become refractory or recurrent after treatment with these antibody-containing regimens.
Treatment with agonistic, antagonistic or blocking antibodies against co-stimulatory or co-inhibitory molecules (immune checkpoints) has been the field of extensive research and clinical evaluation. Under normal physiological conditions, immune checkpoints are critical for maintaining self-tolerance (i.e., preventing autoimmunity) and protecting tissues from damage when the immune system responds to pathogenic infections. It is also now clear that tumors choose certain immune checkpoint pathways as the primary mechanism of immune tolerance (especially against tumor antigen specific T cells) (Pardoll DM., nat Rev Cancer,12:252-64,2012). Thus, treatments with antibodies to immune checkpoint molecules include, for example, CTLA-4 (Yiprim), PD-1 (na Wu Liyou mab; palbocizumab; pistrizumab) and PD-L1 (BMS-936559; MPLD3280A; MEDI4736; MSB 0010718C) (see, for example, philips and Atkins, international Immunology,27 (1); 39-46, oct 2014), and OX-40, CD137, GITR, LAG3, TIM-3 and VISTA (see, for example, sharon et al, chin J cancer, 33 (9): 434-444,Sep 2014;Hodi et al, N Engl J Med,2010; topalian et al, N Engl JMed, 366:2443-54) are being evaluated as novel alternative immunotherapies to treat patients with proliferative diseases such as cancer, and in particular patients with refractory and/or recurrent cancer.
Treatment using Chimeric Antigen Receptor (CAR) T cell therapy is an immunotherapy in which the patient's own T cells are isolated in the laboratory, redirected with synthetic receptors that recognize specific antigens or proteins, and re-infused into the patient. CARs are synthetic molecules comprising at least: (1) an antigen binding region, typically derived from an antibody, (2) a transmembrane domain that anchors the CAR into a T cell, and (3) 1 or more intracellular T cell signaling domains. CARs redirect T cell specificity to antigens in a manner independent of Human Leukocyte Antigen (HLA) and overcome problems associated with T cell tolerance (Kalos M and June CH, immunity,39 (1): 49-60,2013). Over the last 5 years, at least 15 clinical trials of CAR-T cell therapies have been published. A new exciting event around CAR-T cell therapy began at month 2011, when researchers at the university of pennsylvania (Penn) published a report that for 3 patients with refractory Chronic Lymphocytic Leukemia (CLL), they received long term remission after a single dose of CAR T cells against CD 19 (Porter DL et al, N Engl J med, 365 (8): 725-733, 2011).
Natural Killer (NK) cells are known to mediate anti-cancer effects in comparison to donor T cells without the risk of eliciting graft versus host disease (GvHD). Accordingly, alloreactive NK cells are now also a considerable focus of interest as suitable and powerful effector cells for cancer cell therapies. Several human NK cell lines have been established, for example, NK-92, HANK-1, KHYG-1, NK-YS, NKG, YT, YTS, NKL and NK3.3 (Kornbluth, J. Et al, J. Immunol.134,728-735,1985; cheng, M. Et al, front. Med.6:56,2012), and a variety of NK cells (CAR-NK) expressing CAR have been generated. Immunotherapy using CAR-expressing NK cells (CAR-NK) is an active area of research and clinical evaluation (see, e.g., glinke et al, front Pharmacol,6 (21): 1-7,2015, month 2).
Bispecific T cell engagement molecules
Figure BDA0004131772340000281
A class of bispecific single chain antibodies is constituted for polyclonal activation and redirection of cytotoxic T cells against pathogenic target cells. />
Figure BDA0004131772340000282
Is bispecific with respect to the surface target antigen of cancer cells and CD3 on T cells. />
Figure BDA0004131772340000283
Any kind of cytotoxic T cells can be linked to cancer cells without reliance on T cell receptor specificity, co-stimulation or peptide antigen presentation. A unique set of properties have not been reported for any other class of bispecific antibody constructs, i.e., excellent potency and efficacy against target cells at low T cell numbers without the need for T cell co-stimulation (Baeuerle et al, cancer Res,69 (12): 4941-4, 2009). To date, biTE antibodies have been constructed against more than 10 different target antigens, including CD19, epCAM, her2/neu, EGFR, CD66e (or CEA, CEACAM 5), CD33, ephA2, and MCSP (or HMW-MAA) (supra). Use- >
Figure BDA0004131772340000284
Antibodies such as bolaformab (Nagorsen, d. Et al, leukemia)&Treatment of Lymphoma50 (6): 886-891, 2009) and solitab (Amann et al Journal of Immunotherapy32 (5): 452-464, 2009) is being evaluated clinically.
In some embodiments, the second therapy will comprise administration of a PARP inhibitor. Poly (ADP-ribose) polymerase (PARP) is a family of enzymes involved in a variety of activities in response to DNA damage. PARP-1 is a key DNA repair enzyme that mediates Single Strand Break (SSB) repair via the Base Excision Repair (BER) pathway. PARP inhibitors have been shown to selectively kill tumor cells bearing BRCA1 and BRCA2 mutations. In addition, preclinical and preliminary clinical data indicate that PARP inhibitors are also selectively cytotoxic to tumors with defects in homologous recombination repair caused by gene dysfunction other than BRCA1 or BRCA 2. In some embodiments, the PARP inhibitor is selected from the group consisting of: ABT-767, AZD 2461, BGB-290, BGP 15, CEP 9722, E7016, E7449, fluxapari, INO1001, JPI 289, MP 124, nilaparib, olapari, ONO2231, ruaparib, SC 101914, tazopari, vitamin Li Pali, WW 46, or salts or derivatives thereof. In some embodiments, the anti-PARP therapy is administered at a dose equivalent to about 100mg, about 200mg, or about 300mg of nilaparil or a salt or derivative thereof. In some embodiments, the anti-PARP therapy is administered at a dose equivalent to about 100mg of nilaparil or a salt or derivative thereof. In some embodiments, the anti-PARP therapy is administered at a dose equivalent to about 200mg of nilaparil or a salt or derivative thereof. In certain embodiments, the anti-PARP therapy is administered at a dose equivalent to about 300mg of nilaparil or a salt or derivative thereof.
The AXL variants can be administered prior to, concurrently with, or after the second therapy, typically for at least about 1 week, at least about 5 days, at least about 3 days, at least about 1 day. The AXL variants may be delivered in a single dose or may be delivered in multiple doses, for example, over a period of time (including daily, every two days, every half-week, weekly, etc.). The effective dosage will vary with the route of administration, the particular agent, the dosage of the cytoreductive agent, etc., and can be determined empirically by one of skill in the art. The useful range of polypeptides for i.v. administration can be determined empirically, for example, at least about 0.1mg/kg body weight; at least about 0.5mg/kg body weight; at least about 1mg/kg body weight; at least about 2.5mg/kg body weight; at least about 5mg/kg body weight; at least about 10mg/kg body weight; at least about 20mg/kg body weight; or more. In some embodiments, the soluble AXL variant polypeptide will be administered as an IV infusion at a dose of 20mg/kg per week within 30 minutes or 60 minutes. In some embodiments, the soluble AXL variant polypeptide will be administered as an IV infusion at a dose of 15mg/kg per week within 30 minutes or 60 minutes. In some embodiments, the soluble AXL variant polypeptide will be administered as an IV infusion at a dose of 10mg/kg per week within 30 minutes or 60 minutes. In some embodiments, the soluble AXL variant polypeptide will be administered as an IV infusion at a dose of 5mg/kg per week within 30 minutes or 60 minutes. In some embodiments, the soluble AXL variant polypeptide will be administered as an IV infusion at a dose of 2.5mg/kg per week over 30 minutes or 60 minutes. In some embodiments, the soluble AXL variant polypeptide will be administered as an IV infusion at a dose of 1mg/kg per week within 30 minutes or 60 minutes. In some embodiments, the soluble AXL variant polypeptide will be administered as an IV infusion at a dose of 20mg/kg every 14 days within 30 minutes or 60 minutes. In some embodiments, the soluble AXL variant polypeptide will be administered as an IV infusion at a dose of 15mg/kg every 14 days within 30 minutes or 60 minutes. In some embodiments, the soluble AXL variant polypeptide will be administered as an IV infusion at a dose of 10mg/kg every 14 days within 30 minutes or 60 minutes. In some embodiments, the soluble AXL variant polypeptide will be administered as an IV infusion at a dose of 5mg/kg every 14 days within 30 minutes or 60 minutes. In some embodiments, the soluble AXL variant polypeptide will be administered as an IV infusion at a dose of 2.5mg/kg every 14 days within 30 minutes or 60 minutes. In some embodiments, the soluble AXL variant polypeptide will be administered as an IV infusion at a dose of 1mg/kg every 14 days within 30 minutes or 60 minutes.
In some embodiments, the treatment regimen entails administration once every two weeks, or once a month, or once every 3 to 6 months. The therapeutic entity of the present invention is typically administered at more than one occasion (on multiple occasions). The interval between single doses may be weekly, monthly or yearly. The intervals may also be irregular, as indicated by measuring the blood level of the therapeutic entity in the patient. Alternatively, the therapeutic entities of the present invention may be administered in a slow release formulation, in which case less frequent administration is required. The dosage and frequency will vary depending on the half-life of the polypeptide in the patient.
In still other embodiments, the therapeutic entities of the present invention are generally administered in a pharmaceutical composition comprising an active therapeutic agent, as well as various other pharmaceutically acceptable components. (see Remington's Pharmaceutical Sciences,15.sup.th ed., mack Publishing Company, easton, pa., 1980). The preferred form depends on the intended mode of administration and therapeutic application. Depending on the desired formulation, the composition may also comprise a pharmaceutically acceptable non-toxic carrier or diluent, which is defined as a vehicle commonly used to formulate pharmaceutical compositions for animal or human administration. The diluent is selected so as not to affect the biological activity of the combination. Examples of such diluents are distilled water, physiological phosphate buffered saline, ringer's solution, dextrose solution, and hank's solution. In addition, the pharmaceutical compositions or formulations may also contain other carriers, adjuvants or nontoxic, non-therapeutic, non-immunogenic stabilizers and the like.
In still other embodiments, the pharmaceutical compositions of the invention may also include large, slowly metabolizing macromolecules such as proteins, polysaccharides such as chitosan, polylactic acid, polyglycolic acid, and copolymers (such as latex functionalized Sepharose TM Agarose, cellulose, etc.), polyamino acids (polymeric amino acids), amino acid copolymers and lipid aggregates (such as oil droplets or liposomes). In addition, these carriers may act as immunostimulants (i.e., adjuvants).
In prophylactic applications, relatively low doses are administered at relatively infrequent intervals over a long period of time. Some patients continue to receive treatment for their remaining life. In therapeutic applications, relatively high doses are sometimes required at relatively short intervals until the progression of the disease is reduced or terminated, and preferably until the patient shows a partial or complete improvement in the symptoms of the disease. Thereafter, the present patent may be administered in a prophylactic regimen.
In yet some other embodiments, for prophylactic use, the pharmaceutical composition or medicament is administered to a patient susceptible to or otherwise at risk of a disease or condition, including biochemical, histological and/or behavioral symptoms of the disease, complications of the disease, and intermediate pathological phenotypes that occur during the progression of the disease, in an amount sufficient to eliminate or reduce the risk of the disease, reduce the severity of the disease, or delay the onset of the disease.
In yet some other embodiments, for therapeutic use, the therapeutic entity of the invention is administered to a patient suspected of suffering from or already suffering from a disease (including its complications and intermediate pathological phenotypes in disease progression) in an amount sufficient to cure or at least partially halt symptoms (biochemical, histological and/or behavioral) of the disease. An amount sufficient to achieve therapeutic or prophylactic treatment is defined as a therapeutically effective dose or a prophylactically effective dose. In both prophylactic and therapeutic regimens, the agent is typically administered in several doses until a sufficient response is obtained. Typically, the response is monitored and repeated doses are administered if there is a recurrence of the cancer.
According to the present invention, a composition for treating primary or metastatic cancer may be administered by: parenteral, topical, intravenous, intratumoral, oral, subcutaneous, intra-arterial, intracranial, intraperitoneal, intranasal, or intramuscular. The most typical route of administration is intravenous or intratumoral, but other routes may be equally effective.
For parenteral administration, the compositions of the invention may be administered in injectable dosages of solutions or suspensions of the substance in a physiologically acceptable diluent and pharmaceutical carrier, which may be sterile liquids such as water, oil, saline, glycerol or ethanol. In addition, auxiliary substances such as wetting or emulsifying agents, surfactants, pH buffering substances, and the like may be present in the composition. Other components of the pharmaceutical composition are those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil and mineral oil. In general, glycols such as propylene glycol or polyethylene glycol are preferred liquid carriers, particularly for injectable solutions. The antibodies and/or polypeptides may be administered in the form of a depot injection or implant (implant preparation) which may be formulated in a manner that allows for sustained release of the active ingredient. In some embodiments, the composition comprises 1mg/mL of the polypeptide formulated in an aqueous buffer (adjusted to pH 7.4 with HCl or NaOH) consisting of 10mM Tris, 210mM sucrose, 51mM L-arginine, 0.01% polysorbate 20.
Typically, the compositions are prepared as injectables (injectables) as liquid solutions or suspensions; may also be prepared in solid form suitable for dissolution or suspension in a liquid vehicle prior to injection. The formulation may also be emulsified or encapsulated in liposomes or microparticles (such as polylactic acid, polyglycolide or copolymers for enhanced assistance), as discussed above. Langer, science 249:1527,1990 and Hanes, advanced Drug Delivery Reviews 28:97-119,1997. The agents of the invention may be administered in the form of a depot injection or implant preparation which may be formulated in a manner which allows sustained or pulsatile release of the active ingredient.
Additional formulations suitable for other modes of administration include oral, intranasal and pulmonary formulations, suppositories and transdermal applications.
For suppositories, binders and carriers include, for example, polyalkylene glycols or triglycerides; such suppositories may be formed from mixtures containing the active ingredient in the range of 0.5% to 10%, preferably 1% -2%. Oral formulations include excipients such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, and magnesium carbonate. These compositions take the form of solutions, suspensions, tablets, pills, capsules, sustained release formulations or powders and contain from 10% to 95%, preferably from 25% to 70% of the active ingredient.
Topical application may result in transdermal or intradermal delivery. Topical application may be facilitated by co-administration of the agent with cholera toxin or detoxified derivatives or subunits thereof or other similar bacterial toxins. Glenn et al, nature 391:851,1998. Co-administration may be achieved by using linked molecules obtained as a mixture or by chemical cross-linking or as components of fusion proteins. Alternatively, transdermal delivery may be achieved using a skin patch or using a transfer body (transferome). Paul et al, eur.J.Immunol.25:3521-24,1995; cevc et al, biochem. Biophys. Acta 1368:201-15,1998.
Pharmaceutical compositions are typically formulated to be sterile, substantially isotonic, and fully compliant with all good manufacturing practice (Good Manufacturing Practice, GMP) regulations of the united states food and drug administration. Preferably, a therapeutically effective dose of the polypeptide composition described herein will provide a therapeutic benefit without causing substantial toxicity.
Toxicity of the proteins described herein can be determined in cell culture or experimental animals by standard pharmaceutical procedures, e.g., by determining LD 50 (dose lethal to 50% of population) or LD 100 (100% lethal dose to population). The dose ratio between toxic and therapeutic effects is the therapeutic index. The data obtained from these cell culture assays and animal studies can be used in formulating a range of dosage for use in humans that is not toxic. The dosages of the proteins described herein preferably fall within a range of circulating concentrations that include an effective dose with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. The exact formulation, route of administration and dosage may be selected by the physician individual in view of the patient's condition. (see, e.g., fingl et al, 1975,In:The Pharmacological Basis of Therapeutics,Ch.1).
Kits comprising the compositions of the invention and instructions for use are also within the scope of the invention. The kit may also include at least one additional agent, such as a cytoreductive drug. The composition may be provided in the form of a unit dosage formulation. The kit typically includes a label that indicates the intended use of the contents of the kit. The term label includes any text or recording material on or provided with the cartridge or any text or recording material otherwise attached to the cartridge.
Example 1
The present inventors have recently completed a phase 1b dose escalation study (AVB 500-OC-002) evaluating AVB-500 in combination with Pegylated Liposomal Doxorubicin (PLD) or paclitaxel (paclitaxel) for platinum-resistant ovarian cancer (PROC) patients. Dosing regimen was AVB-500 as IV infusion over 60 minutesThe infusion administration was continued for a treatment period of 28 days, starting on day 1. The physician's choice of chemotherapy can be followed, but currently includes 1) paclitaxel at 80mg/m weekly for a 28 day treatment cycle 2 Is administered as an IV infusion over 60 minutes, or 2) PLD at 40mg/m on day 1 of the 28 day treatment cycle 2 Is administered as an IV infusion over 60 minutes. Patient selection included ovarian cancer patients who had previously received 1-3 line therapy, advanced, measurable disease, no platinum interval of 6mo or less following the most recent platinum containing regimen. Positive data for phase 1b studies are shown to be 10mg/kg and show a relationship showing a strong correlation between AVB-500 blood levels and anti-tumor response in platinum-resistant patients.
The safety of AVB-500 has been studied in 84 subjects, including 31 healthy volunteers in phase 1a study and 53 patients with PROC in phase 1b study (40 in 10mg/kg cohort, 6 in 15mg/kg cohort, and 7 in 20mg/kg cohort). The main objective of PROC studies was to evaluate the safety and pharmacokinetics of AVB-500 in combination with Paclitaxel (PAC) or Pegylated Liposomal Doxorubicin (PLD). Secondary endpoints included Objective Response Rate (ORR), CA-125 response, disease control rate, progression Free Survival (PFS), overall survival, pharmacokinetic (PK) profile, GAS6 serum levels, and anti-drug antibody titers. Analysis of all safety data to date shows that AVB-500 is well tolerated with no dose limiting toxicity or unexpected safety signs. To date, there is no AVB-500 related SAE report.
Previous analysis of data from 31 patients in a 10mg/kg cohort showed that blood trough levels of AVB-500 showed statistically significant correlation with efficacy, as patients reaching the Minimum Effective Concentration (MEC) >13.8mg/L showed greater response probability and prolonged PFS. The updated model using actual data from all enrolled patients showed that 60%, 85% and 93% of patients reached MEC at doses of 10mg/kg, 15mg/kg and 20mg/kg, respectively.
The primary efficacy can be summarized as follows: in a 10mg/kg cohort (37 of 40 patients were rated): in patients treated with AVB-500 in combination with PAC, ORR was 31% (5/16), 1 Complete Response (CR). Patients given AVB-500 plus PAC and reaching MEC of AVB-500 showed an improved ORR of 50% (4/8), 1 CR. PFS for patients reaching MEC of AVB-500 was 7.5 months, while patients below MEC were 2.75 months (p=0.0062). In all patients that can be evaluated, the ORR is 21.6% (8/37), regardless of whether MEC or PAC or PLD is used. In a 15mg/kg cohort (5 of 6 patients were rated): all 5 patients in this cohort showed clinical benefit, 1 CR (CR was continued to be shown 3 months after cessation of chemotherapy when AVB-500 was used as a single dose), 2 PR and 2 SD. In a 20mg/kg cohort (7 of 7 patients were rated): of the 7 patients in this cohort, there were 1 depth PR (CR with target lesions; not confirmed), 1 SD, and 5 PD. 15mg/kg has been selected for use as the recommended phase 2 dose.
Table 1 shows the overall patient response to targeted therapeutic AVB-500 in combination with Paclitaxel (PAC) or PLD.
TABLE 1
Figure BDA0004131772340000341
Notably, AVB-500 plus PAC was shown to perform better than AVB-500 plus PLD because the AVB-500 plus PAC data showed 35% ORR (8/23, including 2 CRs) compared to 15% ORR (4/26) for AVB-500 plus PLD in patients. AVB-500 plus chemotherapy was also shown to perform better in patients not previously exposed to bevacizumab, because AVB-500 produced 60% ORR (6/10, including 2 CRs) when combined with PAC and 19% ORR (3/16) when combined with PLD in a subgroup analysis of patients not previously exposed to bevacizumab in their previous line of therapy. For reference, the control arm of the AURELIA study (NCT 00976911) showed an ORR of 30.2% (16/55) for PAC alone and 7.8% (5/64) for PLD alone.
To evaluate the biomarker strategy, patient tissue is examined from the time of patient diagnosis. This approach solves the problem of the presence of soluble AXL in the tissue at the time of the initial oncologic surgery or clinical biopsy. This was done in combination with the use of a proprietary serum GAS6 Pharmacodynamic (PD) assay developed to guide dose selection in AVB-500 clinical trials. Together, these two assays can be used to establish specific criteria for treatment and patient selection for such targeted therapies. This assay also appears to help monitor the treatment response, allowing the clinician to flexibly grasp and get guidance about better treatment opportunities, and turn on Progression Free Survival (PFS) and Overall Response Rate (ORR) for the patient.
Table 2 shows the overall patient response of AVB-500 in combination with paclitaxel targeted therapy in relation to the baseline serum sAXL/GAS6 ratio.
TABLE 2
Figure BDA0004131772340000351
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CBR = clinical benefit rate (orr+sd); mOS = median total survival; mPFS = median progression-free survival
Table 3 shows the overall patient response of AVB-500 in combination with paclitaxel targeted therapy, including either non-or previously received bevacizumab, correlated with baseline serum sAXL/GAS6 ratio.
TABLE 3 Table 3
Figure BDA0004131772340000352
Figure BDA0004131772340000361
* Studies are underway and thus data may change; * Mec=minimum effective concentration (13.8 mg/L)
1 patient with 10mg/kg and 1 patient with 15mg/kg have CR; one patient with CR at 15mg/kg continued to show CR at C13D1 with AVB-500 alone 6 months after paclitaxel withdrawal
When the response is examined by dose and the ratio of sAXL/GAS6 in the patient is considered to vary with the response, a clear pattern of application of this biomarker strategy appears in the study. The plasma levels of the sAXL/GAS6 ratio appeared to correlate well with the response to AVB-500 (FIG. 1), and this ratio measurement method has emerged as a key tool for future patient stratification. As depicted in fig. 2 and table 2, the serum sAXL/GAS6 ratio correlated well with the response to AVB-500+ chemotherapy and was still an important predictor of RECIST response in this sample (auc=0.7833; p=0.047). Patients with a/G ratio exceeding 0.773 are more significantly likely to reach RECIST responses, with a calculated sensitivity of 100% and specificity of 60%.
Patients with a high sAXL/GAS6 ratio had 30% ORR (10/33) compared to patients with a low AXL/GAS6 ratio of 0% ORR (0/15) throughout the phase 1b cohort. In the PAC cohort, patients with a high sAXL/GAS6 ratio had 43% ORR (6/14) compared to patients with a low sAXL/GAS6 ratio having 0% ORR (0/7). Notably, patients with a high sAXL/GAS6 ratio who had not previously received bevacizumab reached 75% ORR (6/8). Historically, high sAXL has been associated with poor prognosis. Surprisingly, however, AVB-500 plus PAC or PLD appeared to improve the clinical outcome of this population (see fig. 3 and 4).
By extension, this data provides a correlation with serum or tissue present in the tissue or serum AXL and GAS6 as prognostic or diagnostic markers of disease pathology and patient acceptance of AXL decoy protein targeted therapy. And importantly, while historically high AXL expression is associated with poor cancer prognosis, AVB-500 appears to have higher activity in populations with elevated sAXL and suggests that methods using the sAXL/GAS6 ratio as a biomarker would provide better patient stratification and would be a prognostic marker that would uniquely inform clinicians and provide important treatments for cancer patients using such targeted agents, thereby advancing the level of the art.
All publications and patents cited in this specification are herein incorporated by reference as if each individual publication or patent were specifically and individually indicated to be incorporated by reference and all publications and patents cited in this specification are herein incorporated by reference to disclose and describe the methods and/or materials in connection with which the publications are cited. The citation of any publication is for its disclosure prior to the filing date and should not be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Furthermore, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed.
As will be apparent to those of skill in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has discrete components and features that can be readily separated from or combined with the features of any of the other several embodiments without departing from the scope or spirit of the present invention. Any recited method may be performed in the order in which the events are recited or in any other order that is logically possible. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments.
Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be readily apparent to those of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the spirit or scope of the invention and without intending to limit the scope of the invention which is limited only by the appended claims.
Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. It is intended that such equivalents be covered by the appended claims.
Sequence listing
The nucleic acid and amino acid sequences listed in the appended sequence listing are shown using standard alphabetical abbreviations for nucleotide bases and three letter codes for amino acids as defined in 37 c.f.r.1.822.
SEQ ID NO. 1-human AXL polypeptide amino acid sequence
Figure BDA0004131772340000371
SEQ ID NO. 2-exemplary soluble AXL polypeptide-FC fusion.
Figure BDA0004131772340000381
/>
Sequence listing
<110> Alasvivus Co
<120> methods for diagnosing cancer using AXL decoy receptor
<130> CACAB1.0012WO
<160> 2
<170> PatentIn version 3.5
<210> 1
<211> 887
<212> PRT
<213> Homo sapiens (Homo sapiens)
<400> 1
Met Gly Arg Val Pro Leu Ala Trp Cys Leu Ala Leu Cys Gly Trp Ala
1 5 10 15
Cys Met Ala Pro Arg Gly Thr Gln Ala Glu Glu Ser Pro Phe Val Gly
20 25 30
Asn Pro Gly Asn Ile Thr Gly Ala Arg Gly Leu Thr Gly Thr Leu Arg
35 40 45
Cys Gln Leu Gln Val Gln Gly Glu Pro Pro Glu Val His Trp Leu Arg
50 55 60
Asp Gly Gln Ile Leu Glu Leu Ala Asp Ser Thr Gln Thr Gln Val Pro
65 70 75 80
Leu Gly Glu Asp Glu Gln Asp Asp Trp Ile Val Val Ser Gln Leu Arg
85 90 95
Ile Thr Ser Leu Gln Leu Ser Asp Thr Gly Gln Tyr Gln Cys Leu Val
100 105 110
Phe Leu Gly His Gln Thr Phe Val Ser Gln Pro Gly Tyr Val Gly Leu
115 120 125
Glu Gly Leu Pro Tyr Phe Leu Glu Glu Pro Glu Asp Arg Thr Val Ala
130 135 140
Ala Asn Thr Pro Phe Asn Leu Ser Cys Gln Ala Gln Gly Pro Pro Glu
145 150 155 160
Pro Val Asp Leu Leu Trp Leu Gln Asp Ala Val Pro Leu Ala Thr Ala
165 170 175
Pro Gly His Gly Pro Gln Arg Ser Leu His Val Pro Gly Leu Asn Lys
180 185 190
Thr Ser Ser Phe Ser Cys Glu Ala His Asn Ala Lys Gly Val Thr Thr
195 200 205
Ser Arg Thr Ala Thr Ile Thr Val Leu Pro Gln Gln Pro Arg Asn Leu
210 215 220
His Leu Val Ser Arg Gln Pro Thr Glu Leu Glu Val Ala Trp Thr Pro
225 230 235 240
Gly Leu Ser Gly Ile Tyr Pro Leu Thr His Cys Thr Leu Gln Ala Val
245 250 255
Leu Ser Asn Asp Gly Met Gly Ile Gln Ala Gly Glu Pro Asp Pro Pro
260 265 270
Glu Glu Pro Leu Thr Ser Gln Ala Ser Val Pro Pro His Gln Leu Arg
275 280 285
Leu Gly Ser Leu His Pro His Thr Pro Tyr His Ile Arg Val Ala Cys
290 295 300
Thr Ser Ser Gln Gly Pro Ser Ser Trp Thr His Trp Leu Pro Val Glu
305 310 315 320
Thr Pro Glu Gly Val Pro Leu Gly Pro Pro Glu Asn Ile Ser Ala Thr
325 330 335
Arg Asn Gly Ser Gln Ala Phe Val His Trp Gln Glu Pro Arg Ala Pro
340 345 350
Leu Gln Gly Thr Leu Leu Gly Tyr Arg Leu Ala Tyr Gln Gly Gln Asp
355 360 365
Thr Pro Glu Val Leu Met Asp Ile Gly Leu Arg Gln Glu Val Thr Leu
370 375 380
Glu Leu Gln Gly Asp Gly Ser Val Ser Asn Leu Thr Val Cys Val Ala
385 390 395 400
Ala Tyr Thr Ala Ala Gly Asp Gly Pro Trp Ser Leu Pro Val Pro Leu
405 410 415
Glu Ala Trp Arg Pro Gly Gln Ala Gln Pro Val His Gln Leu Val Lys
420 425 430
Glu Pro Ser Thr Pro Ala Phe Ser Trp Pro Trp Trp Tyr Val Leu Leu
435 440 445
Gly Ala Val Val Ala Ala Ala Cys Val Leu Ile Leu Ala Leu Phe Leu
450 455 460
Val His Arg Arg Lys Lys Glu Thr Arg Tyr Gly Glu Val Phe Glu Pro
465 470 475 480
Thr Val Glu Arg Gly Glu Leu Val Val Arg Tyr Arg Val Arg Lys Ser
485 490 495
Tyr Ser Arg Arg Thr Thr Glu Ala Thr Leu Asn Ser Leu Gly Ile Ser
500 505 510
Glu Glu Leu Lys Glu Lys Leu Arg Asp Val Met Val Asp Arg His Lys
515 520 525
Val Ala Leu Gly Lys Thr Leu Gly Glu Gly Glu Phe Gly Ala Val Met
530 535 540
Glu Gly Gln Leu Asn Gln Asp Asp Ser Ile Leu Lys Val Ala Val Lys
545 550 555 560
Thr Met Lys Ile Ala Ile Cys Thr Arg Ser Glu Leu Glu Asp Phe Leu
565 570 575
Ser Glu Ala Val Cys Met Lys Glu Phe Asp His Pro Asn Val Met Arg
580 585 590
Leu Ile Gly Val Cys Phe Gln Gly Ser Glu Arg Glu Ser Phe Pro Ala
595 600 605
Pro Val Val Ile Leu Pro Phe Met Lys His Gly Asp Leu His Ser Phe
610 615 620
Leu Leu Tyr Ser Arg Leu Gly Asp Gln Pro Val Tyr Leu Pro Thr Gln
625 630 635 640
Met Leu Val Lys Phe Met Ala Asp Ile Ala Ser Gly Met Glu Tyr Leu
645 650 655
Ser Thr Lys Arg Phe Ile His Arg Asp Leu Ala Ala Arg Asn Cys Met
660 665 670
Leu Asn Glu Asn Met Ser Val Cys Val Ala Asp Phe Gly Leu Ser Lys
675 680 685
Lys Ile Tyr Asn Gly Asp Tyr Tyr Arg Gln Gly Arg Ile Ala Lys Met
690 695 700
Pro Val Lys Trp Ile Ala Ile Glu Ser Leu Ala Asp Arg Val Tyr Thr
705 710 715 720
Ser Lys Ser Asp Val Trp Ser Phe Gly Val Thr Met Trp Glu Ile Ala
725 730 735
Thr Arg Gly Gln Thr Pro Tyr Pro Gly Val Glu Asn Ser Glu Ile Tyr
740 745 750
Asp Tyr Leu Arg Gln Gly Asn Arg Leu Lys Gln Pro Ala Asp Cys Leu
755 760 765
Asp Gly Leu Tyr Ala Leu Met Ser Arg Cys Trp Glu Leu Asn Pro Gln
770 775 780
Asp Arg Pro Ser Phe Thr Glu Leu Arg Glu Asp Leu Glu Asn Thr Leu
785 790 795 800
Lys Ala Leu Pro Pro Ala Gln Glu Pro Asp Glu Ile Leu Tyr Val Asn
805 810 815
Met Asp Glu Gly Gly Gly Tyr Pro Glu Pro Pro Gly Ala Ala Gly Gly
820 825 830
Ala Asp Pro Pro Thr Gln Pro Asp Pro Lys Asp Ser Cys Ser Cys Leu
835 840 845
Thr Ala Ala Glu Val His Pro Ala Gly Arg Tyr Val Leu Cys Pro Ser
850 855 860
Thr Thr Pro Ser Pro Ala Gln Pro Ala Asp Arg Gly Ser Pro Ala Ala
865 870 875 880
Pro Gly Gln Glu Asp Gly Ala
885
<210> 2
<211> 426
<212> PRT
<213> Artificial (Artifical)
<220>
<223> soluble AXL polypeptide-Fc fusion
<400> 2
Glu Glu Ser Pro Phe Val Ser Asn Pro Gly Asn Ile Thr Gly Ala Arg
1 5 10 15
Gly Leu Thr Gly Thr Leu Arg Cys Gln Leu Gln Val Gln Gly Glu Pro
20 25 30
Pro Glu Val His Trp Leu Arg Asp Gly Gln Ile Leu Glu Leu Val Asp
35 40 45
Ser Thr Gln Thr Gln Val Pro Leu Gly Glu Asp Glu Gln Gly Asp Trp
50 55 60
Ile Val Ala Ser Gln Leu Arg Ile Thr Ser Leu Gln Leu Ser Asp Thr
65 70 75 80
Gly Gln Tyr Gln Cys Leu Val Phe Leu Gly His Gln Thr Phe Val Ser
85 90 95
Gln Pro Gly Tyr Val Arg Leu Glu Gly Leu Pro Tyr Phe Leu Glu Glu
100 105 110
Pro Glu Asp Arg Thr Val Ala Ala Asn Thr Pro Phe Asn Leu Ser Cys
115 120 125
Gln Ala Gln Gly Pro Pro Glu Pro Val Asp Leu Leu Trp Leu Gln Asp
130 135 140
Ala Val Pro Leu Ala Thr Ala Pro Gly His Gly Pro Gln Arg Ser Leu
145 150 155 160
His Val Pro Gly Leu Asn Lys Thr Ser Ser Phe Ser Cys Glu Ala His
165 170 175
Asn Ala Lys Gly Val Thr Thr Ser Arg Thr Ala Thr Ile Thr Val Leu
180 185 190
Pro Gln Gln Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro
195 200 205
Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro
210 215 220
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
225 230 235 240
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
245 250 255
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
260 265 270
Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
275 280 285
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
290 295 300
Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
305 310 315 320
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu
325 330 335
Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
340 345 350
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
355 360 365
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
370 375 380
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
385 390 395 400
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
405 410 415
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
420 425

Claims (26)

1. A method of diagnosing and selecting a subject with cancer for treatment with an AXL binding agent, the method comprising: i) Detecting a level of sAXL activity in a biological sample from the subject; ii) detecting the level of soluble GAS6 activity in a biological sample from the subject; and iii) selecting the subject for treatment when the sAXL/GAS6 ratio is high.
2. The method of claim 1, wherein the sAXL/GAS6 ratio is selected from the group consisting of: greater than 0.8, greater than 0.85, greater than 0.9, greater than 0.95, greater than 1.0, greater than 1.05, greater than 1.1, greater than 1.15, greater than 1.2, greater than 1.25, greater than 1.3, greater than 1.35, greater than 1.4, greater than 1.45, greater than 1.5, greater than 2.0, greater than 2.5, and greater than 3.0.
3. A method of diagnosing and selecting a subject with cancer for treatment with an AXL binding agent, the method comprising: i) Detecting a level of sAXL phosphorylation in a biological sample from the subject; ii) detecting the level of GAS6 activity in a biological sample from the subject; and iii) selecting the subject for treatment with an AXL binding agent when AXL phosphorylation levels and soluble GAS6 levels are high.
4. The method of claim 5, wherein the AXL phosphorylation marker is selected from the group consisting of: tyr698, tyr702, tyr703, tyr779, tyr821, tyr866, and Tyr929.
5. A method for treating or delaying progression of cancer in a subject having cancer, the method comprising administering to the subject a therapeutically effective amount of an AXL binding agent; wherein the sAXL/GAS6 ratio in the biological sample from the subject is high.
6. The method of claim 3, wherein the sAXL/GAS6 ratio is selected from the group consisting of: greater than 0.8, greater than 0.85, greater than 0.9, greater than 0.95, greater than 1.0, greater than 1.05, greater than 1.1, greater than 1.15, greater than 1.2, greater than 1.25, greater than 1.3, greater than 1.35, greater than 1.4, greater than 1.45, greater than 1.5, greater than 2.0, greater than 2.5, and greater than 3.0.
7. The method of any one of claims 1-6, wherein the AXL binding agent is a soluble AXL variant polypeptide.
8. The method of claim 7, wherein the soluble AXL variant polypeptide lacks an AXL transmembrane domain; lack of functional Fibronectin (FN) domains; having one or more Ig1 domains, and optionally having one or more Ig2 domains; and having a set of amino acid modifications to the wild-type AXL sequence (SEQ ID NO: 1) selected from the group consisting of:
1) Gly32Ser, asp87Gly, val92Ala and Gly127Arg,
2) Glu26Gly, val79Met, val92Ala and Gly127Glu; and
3) Gly32Ser, ala72Val, asp87Gly, val92Ala and Gly127Arg;
wherein the modification increases the affinity of the AXL polypeptide for binding to growth arrest-specific protein 6 (GAS 6).
9. The method of claim 8, wherein the soluble AXL variant polypeptide is fused to an Fc region.
10. The method of claim 5, wherein the AXL binding agent is administered in combination with cytoreductive therapy.
11. The method of claim 10, wherein the cytoreductive therapy is radiation therapy.
12. The method of claim 5, wherein the AXL binding agent is administered in combination with a chemotherapeutic agent.
13. The method of claim 12, wherein the chemotherapeutic agent is selected from the group consisting of: daunorubicin, doxorubicin (doxorubicin), epirubicin, idarubicin, anamycin, MEN 10755, etoposide, teniposide, vinblastine, vincristine, vinorelbine (navlbine), vindesine, vindoline, vinblastine, mechlorethamine, cyclophosphamide, melphalan (L-lysosarcosine), carmustine (BCNU), lomustine (CCNU), semustine (methyl-CCNU), streptozomycin, chlorourea, cytarabine (CYTOSAR-U), cytosine arabinoside, fluorouracil (5-FU), fluorouridine (FUdR), thioguanine (6-thioguanine), mercaptopurine (6-MP), pentadine, fluorouracil (5-FU), methotrexate, 10-propargyl-5, 8-bifolate (PDDF, CB 3717), 5, 8-dideoxy (dddf), tetrahydropalmatine (ddha), oxaliplatin, gemfibrozil, and hydroxyzine.
14. The method of claim 5, wherein the AXL binding agent is administered in combination with an immunotherapy.
15. The method of claim 14, wherein the immunotherapy is selected from the group consisting of: treatment with depleting antibodies against specific tumor antigens; treatment with antibody-drug conjugates; treatment with agonistic, antagonistic or blocking antibodies against co-stimulatory or co-inhibitory molecules (immune checkpoints) such as CTLA-4, PD-1, OX-40, CD137, GITR, LAG3, TIM-3 and VISTA; use of bispecific T cell engagement antibodies
Figure FDA0004131772330000031
Treatment such as bordetention; treatment involving administration of biological response modifiers such as IL-2, IL-12, IL-15, IL-21, GM-CSF, IFN- α, IFN- β, and IFN- γ; treatment with therapeutic vaccines such as sipuleucel-T; treatment with a dendritic cell vaccine or a tumor antigen peptide vaccine; treatment using Chimeric Antigen Receptor (CAR) -T cells; treatment with CAR-NK cells; treatment with Tumor Infiltrating Lymphocytes (TILs); using adoptive transferIs described herein, the treatment of anti-tumor T cells (ex vivo expanded and/or TCR transgenic); treatment with TALL-104 cells; and treatment with immunostimulants such as Toll-like receptor (TLR) agonists CpG and imiquimod.
16. The method of claim 5, wherein the AXL binding agent is administered in combination with a poly (ADP-ribose) polymerase (PARP) inhibitor.
17. The method of claim 16, wherein the PARP inhibitor is selected from the group consisting of: ABT-767, AZD 2461, BGB-290, BGP 15, CEP 9722, E7016, E7449, fluxaparide, INO1001, JPI 289, MP 124, nilaparib, olaparide, ONO2231, rupa, SC 101914, taprazoparide, vitamin Li Pali, WW 46, or salts or derivatives thereof, olaparide, rupa, nilaparib, taprazoparide, and valiparib.
18. The method of claim 5, wherein the AXL binding agent is administered in combination with polyethylene glycol liposomal doxorubicin (PLD).
19. The method of claim 1, wherein the AXL binding agent is administered in combination with paclitaxel.
20. The method of any one of claims 10-19, wherein the combination has a synergistic effect.
21. The method of claim 5, wherein the cancer overexpresses the biomarkers GAS6 and/or AXL.
22. The method of claim 5, wherein the cancer is a recurrent cancer.
23. The method of claim 5, wherein the cancer is resistant to standard therapy.
24. The method of claim 5, wherein the cancer is a chemotherapy-resistant cancer.
25. The method of claim 5, wherein the cancer is a platinum-resistant cancer.
26. The method of any one of claims 5-25, wherein the cancer is selected from the group consisting of: b-cell lymphoma, lung cancer (small cell lung cancer and non-small cell lung cancer), bronchi cancer, colorectal cancer, prostate cancer, breast cancer, pancreatic cancer, gastric cancer, ovarian cancer, bladder cancer, brain or central nervous system cancer, peripheral nervous system cancer, esophageal cancer, cervical cancer, melanoma, uterine or endometrial cancer, cancer of the oral cavity or pharynx, liver cancer, kidney cancer, biliary tract cancer, small intestine or appendiceal cancer, salivary gland cancer, thyroid cancer, adrenal gland cancer, osteosarcoma, chondrosarcoma, liposarcoma, testicular cancer and malignant fibrous histiocytoma, skin cancer, head and neck cancer, lymphoma, sarcoma, multiple myeloma and leukemia.
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